Steroid-containing sustained release intraocular implants and related methods

ABSTRACT

Biocompatible intraocular implants include a steroid and a polymer associated with each other to facilitate release of the steroid into an eye for a period of time greater than about two months. The steroid may be associated with a biodegradable polymer matrix, such as a matrix of a two biodegradable polymers. Or, the steroid may be associated with a polymeric coating having one or more openings effective to permit the steroid to be released into an external environment. The implants may be placed in an eye to treat one or more ocular conditions. The steroid is released from the implant for more than about two months, and may be release for more than several years.

CROSS REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.10/837,356, filed Apr. 30, 2004, the entire content of which applicationis hereby incorporated by reference.

BACKGROUND

The present invention generally relates to devices and methods to treatan eye of a patient, and more specifically to intraocular implants thatprovide extended release of a therapeutic agent to an eye in which theimplant is placed.

Steroids, such as the corticosteroid, fluocinolone acetonide(1,4-pregnadien-6α,9α-difluoro-11β,16α,17,21-tetrol-3,20-dione16,17-acetonide), are usually given topically, systemically, orperiocularly, as an injection, to treat uveitis. All three methods ofdelivery have drawbacks, e.g., topical corticosteroids do not treatdiseases in the back on the eye, systemic corticosteroids are oftenassociated with many unwanted side effects, and periocular injectionsmay sometimes cause globe perforation, periocular fibrosis and ptosis.

An alternative that may circumvent the drawbacks of the above-mentioneddelivery methods is to use sustained-released drug delivery systems. In2000, Jaffe et al. reported using compressed pure fluocinolone acetonidepellets coated with silicone and polyvinyl alcohol as a fluocinolonesustained delivery device (Jaffe, G. J. et al., Journal of Ophthalmologyand Vision Surgery, Vol 41, No. 11, October 2000). They obtained releaserates of 1.9±0.25 μg/day (6 months) and 2.2±0.6 μg/day (45 days) for the2-mg device and 15-mg device, respectively. The duration of release forthe 2-mg and 15-mg device was estimated to be 2.7 and 18.6 years,respectively. U.S. Pat. Nos. 6,217,895 and 6,548,078 disclose sustainedrelease implants for delivering a corticosteroid, such as fluocinoloneacetonide, to an eye. However, fluocinolone acetonide intravitrealimplants made by Control Delivery Systems (the assignee of U.S. Pat.Nos. 6,217,895 and 6,548,078) were only partially successful and led tothe development of cataracts and increased intraocular pressure.

In addition, intravitreal injection of triamcinolone acetonide(KENALOG®) for treatments of non-infectious uveitis, and macular edemadue to various retinal diseases has appeared to be safe and effective.

Additional biocompatible implants for placement in the eye have beendisclosed in a number of patents, such as U.S. Pat. Nos. 4,521,210;4,853,224; 4,997,652; 5,164,188; 5,443,505; 5,501,856; 5,766,242;5,824,072; 5,869,079; 6,074,661; 6,331,313; 6,369,116; 6,699,493, and6,726,918.

Other intravitreal therapeutic approaches are described in U.S.application Ser. Nos. 10/966,764, filed Oct. 14, 2004; Ser. No.11/039,192, filed Jan. 19, 2005; and Ser. No. 60/587,092, filed Jul. 12,2004.

It would be advantageous to provide eye implantable drug deliverysystems, such as intraocular implants, and methods of using suchsystems, that are capable of releasing a therapeutic agent at asustained or controlled rate for extended periods of time and in amountswith few or no negative side effects.

SUMMARY

The present invention provides new drug delivery systems, and methods ofusing such systems, for extended or sustained drug release into an eye,for example, to achieve one or more desired therapeutic effects. Thedrug delivery systems are in the form of implants or implant elementsthat may be placed in an eye. The present systems and methodsadvantageously provide for extended release times of one or moretherapeutic agents. Thus, the patient in whose eye the implant has beenplaced receives a therapeutic amount of an agent for a long or extendedtime period without requiring additional administrations of the agent.For example, the patient has a substantially consistent level oftherapeutically active agent available for consistent treatment of theeye over a relatively long period of time, for example, on the order ofat least about two months, such as between about two and about sixmonths, or even for about one or about two years or longer afterreceiving an implant. Such extended release times facilitate obtainingsuccessful treatment results.

Intraocular implants in accordance with the disclosure herein comprise atherapeutic component and a drug release sustaining component associatedwith the therapeutic component. In accordance with the presentinvention, the therapeutic component comprises, consists essentially of,or consists of, a steroid. The drug release sustaining component isassociated with the therapeutic component to sustain release of atherapeutically effective amount of the steroid into an eye in which theimplant is placed. The therapeutically effective amount of the steroidis released into the eye for a period of time greater than about twomonths after the implant is placed in the eye.

In one embodiment, the intraocular implants comprise a steroid and abiodegradable polymer matrix. The steroid is associated with abiodegradable polymer matrix that releases drug, such as by degrading,at a rate effective to sustain release of a therapeutically effectiveamount of the steroid from the implant for a time greater or longer thanabout two months from a time the implant is placed in an ocular site orregion of an eye. The intraocular implant is biodegradable orbioerodible and provides a sustained release of the steroid in an eyefor extended periods of time, such as for more than two months, forexample for about three months or more and up to about six months ormore.

The biodegradable polymer component of the foregoing implants may be amixture of biodegradable polymers, wherein at least one of thebiodegradable polymers is a polylactic acid orpoly(lactide-co-glycolide)polymer having a molecular weight less than 40kiloDaltons (kD). Additionally or alternatively, the foregoing implantsmay comprise a first biodegradable polymer having terminal free acidgroups, and a different second biodegradable polymer having terminalfree acid groups. Furthermore, the foregoing implants may comprise amixture of different biodegradable polymers, each biodegradable polymerhaving an inherent viscosity in a range of about 0.16 deciliters/gram(dl/g) to about 0.24 d/g. Examples of suitable biodegradable polymersinclude polymers of lactic acid, glycolic acid, and mixtures thereof.

In another embodiment, intraocular implants comprise a therapeuticcomponent that comprises a steroid, and a polymeric outer layer coveringthe therapeutic component. The polymeric outer layer includes one ormore orifices or openings or holes that are effective to allow a liquidto pass into the implant, and to allow the steroid to pass out of theimplant. The therapeutic component is provided in a core or interiorportion of the implant, and the polymeric outer layer covers or coatsthe core. The polymeric outer layer may include one or morebiodegradable portions. The implant can provide an extended release ofthe steroid for more or longer than about two months, and for more thanabout one year, and even for more than about five or about ten years.

The steroid of the implants disclosed herein may be corticosteroids, orother steroids that are effective in treating ocular conditions. Oneexample of a suitable steroid is fluocinolone or fluocinolone acetonide.Another example of a suitable steroid is triamcinolone or triamcinoloneacetonide. Another example of a suitable steroid is beclomethasone orbeclomethasone dipropionate. In addition, the therapeutic component ofthe present implants may include one or more additional and differenttherapeutic agents that may be effective in treating an ocularcondition.

The implants may be placed in an ocular region to treat a variety ofocular conditions, including conditions that affect an anterior regionor posterior region of an eye. For example, the implants may be used totreat many conditions of the eye, including, without limitation,maculopathies and retinal degeneration, uveitis, retinitis, choroiditis,vascular diseases, and exudative diseases, proliferative disorders,infectious disorders, genetic disorders, tumors, trauma, and surgery,retinal tears or holes, and the like.

Kits in accordance with the present invention may comprise one or moreof the present implants, and instructions for using the implants. Forexample, the instructions may explain how to administer the implants toa patient, and types of conditions that may be treated with theimplants.

Each and every feature described herein, and each and every combinationof two or more of such features, is included within the scope of thepresent invention provided that the features included in such acombination are not mutually inconsistent. In addition, any feature orcombination of features may be specifically excluded from any embodimentof the present invention.

Additional aspects and advantages of the present invention are set forthin the following description and claims, particularly when considered inconjunction with the accompanying drawings and examples.

DRAWINGS

FIG. 1 is a graph showing the cumulative release profiles forbiodegradable fluocinolone acetonide containing implants as determinedin 0.9% saline at 37 degrees Celsius.

FIG. 2 is a graph similar to FIG. 1 showing the cumulative releaseprofiles for biodegradable fluocinolone acetonide containing implantswith different combinations of biodegradable polymers.

FIG. 3 is a graph similar to FIG. 1 showing the cumulative releaseprofiles for biodegradable triamcinolone acetonide containing implants.

FIG. 4 is a graph showing the cumulative release profiles fornon-sterile fluocinolone acetonide containing implants having differenthole configurations.

FIG. 5 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 4.

FIG. 6 is a graph showing the cumulative release profiles for sterilefluocinolone acetonide containing implants having different holeconfigurations.

FIG. 7 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 6.

FIG. 8 is a graph showing the cumulative release profiles fornon-sterile fluocinolone acetonide containing implants having differenthole configurations than those described in FIG. 4.

FIG. 9 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 8.

FIG. 10 is a graph showing the cumulative release profiles for sterilefluocinolone acetonide containing implants having hole configurationssimilar to those described in FIG. 8.

FIG. 11 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 10.

FIG. 12 is a graph showing the cumulative release profiles for sterilefluocinolone acetonide containing implants having different holeconfigurations.

FIG. 13 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 12.

FIG. 14 is a graph showing the cumulative release profiles fornon-sterile fluocinolone acetonide containing implants having differenthole configurations.

FIG. 15 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 14.

FIG. 16 is a graph showing the cumulative release profiles for sterilefluocinolone acetonide containing implants described in FIG. 14.

FIG. 17 is a graph showing the amount of fluocinolone released per dayfor the implants described in FIG. 16.

FIG. 18 is a graph showing the total percent release of triamcinolone asa function of time in phosphate buffered saline for implants containing30% triamcinolone.

FIG. 19 is a graph showing the total percent release of triamcinolone asa function of time in phosphate buffered saline for implants containing50% triamcinolone.

FIG. 20 is a graph showing the total percent release of triamcinolone asa function of time in citrate phosphate buffer for implants containing30% triamcinolone.

FIG. 21 is a graph showing the total percent release of triamcinolone asa function of time in citrate phosphate buffer for implants containing50% triamcinolone.

FIG. 22 is a graph showing the total percent release of beclomethasonepropionate as a function of time in phosphate buffered saline forimplants containing 30% triamcinolone.

FIG. 23 is a graph showing the total percent release of beclomethasonepropionate as a function of time in phosphate buffered saline forimplants containing 50% triamcinolone.

FIG. 24 is a graph showing the total percent release of beclomethasonepropionate as a function of time in citrate phosphate buffer forimplants containing 30% triamcinolone.

FIG. 25 is a graph showing the total percent release of beclomethasonepropionate as a function of time in citrate phosphate buffer forimplants containing 50% triamcinolone.

DESCRIPTION

As described herein, controlled and sustained administration of atherapeutic agent through the use of one or more intraocular implantsmay improve treatment of undesirable ocular conditions. The implantscomprise a pharmaceutically acceptable polymeric composition and areformulated to release one or more pharmaceutically active agents, suchas steroids, over an extended period of time. The implants are effectiveto provide a therapeutically effective dosage of the agent or agentsdirectly to a region of the eye to treat one or more undesirable ocularconditions. Thus, with a single administration, therapeutic agents willbe made available at the site where they are needed and will bemaintained for an extended period of time, rather than subjecting thepatient to repeated injections or, in the case of self-administereddrops, ineffective treatment with only limited bursts of exposure to theactive agent or agents.

An intraocular implant in accordance with the disclosure hereincomprises a therapeutic component and a drug release sustainingcomponent associated with the therapeutic component. In accordance withthe present invention, the therapeutic component comprises, consistsessentially of, or consists of, a steroid. The drug release sustainingcomponent is associated with the therapeutic component to sustainrelease of a therapeutically effective amount of the steroid into an eyein which the implant is placed. The therapeutic amount of the steroid isreleased into the eye for a period of time greater than about two monthsafter the implant is placed in the eye.

Definitions

For the purposes of this description, we use the following terms asdefined in this section, unless the context of the word indicates adifferent meaning.

As used herein, an “intraocular implant” refers to a device or elementthat is structured, sized, or otherwise configured to be placed in aneye. Intraocular implants are generally biocompatible with physiologicalconditions of an eye and do not cause adverse side effects. Intraocularimplants may be placed in an eye without disrupting vision of the eye.

As used herein, a “therapeutic component” refers to a portion of anintraocular implant comprising one or more therapeutic agents orsubstances used to treat a medical condition of the eye. The therapeuticcomponent may be a discrete region of an intraocular implant, or it maybe homogenously distributed throughout the implant. The therapeuticagents of the therapeutic component are typically ophthalmicallyacceptable, and are provided in a form that does not cause adversereactions when the implant is placed in an eye.

As used herein, a “drug release sustaining component” refers to aportion of the intraocular implant that is effective to provide asustained release of the therapeutic agents of the implant. A drugrelease sustaining component may be a biodegradable polymer matrix, orit may be a coating covering a core region of the implant that comprisesa therapeutic component.

As used herein, “associated with” means mixed with, dispersed within,coupled to, covering, or surrounding. With respect to intraocularimplants which comprise a therapeutic component associated with abiodegradable polymer matrix, “associated with” specifically excludesbiodegradable polymeric coatings that may be provided on or around thematrix.

As used herein, an “ocular region” or “ocular site” refers generally toany area of the eyeball, including the anterior and posterior segment ofthe eye, and which generally includes, but is not limited to, anyfunctional (e.g., for vision) or structural tissues found in theeyeball, or tissues or cellular layers that partly or completely linethe interior or exterior of the eyeball. Specific examples of areas ofthe eyeball in an ocular region include the anterior chamber, theposterior chamber, the vitreous cavity, the choroid, the suprachoroidalspace, the conjunctiva, the subconjunctival space, the episcleral space,the intracorneal space, the epicorneal space, the sclera, the parsplana, surgically-induced avascular regions, the macula, and the retina.

As used herein, an “ocular condition” is a disease, ailment or conditionwhich affects or involves the eye or one of the parts or regions of theeye. Broadly speaking the eye includes the eyeball and the tissues andfluids which constitute the eyeball, the periocular muscles (such as theoblique and rectus muscles) and the portion of the optic nerve which iswithin or adjacent to the eyeball.

An anterior ocular condition is a disease, ailment or condition whichaffects or which involves an anterior (i.e. front of the eye) ocularregion or site, such as a periocular muscle, an eye lid or an eye balltissue or fluid which is located anterior to the posterior wall of thelens capsule or ciliary muscles. Thus, an anterior ocular conditionprimarily affects or involves the conjunctiva, the cornea, the anteriorchamber, the iris, the posterior chamber (behind the retina but in frontof the posterior wall of the lens capsule), the lens or the lens capsuleand blood vessels and nerve which vascularize or innervate an anteriorocular region or site.

Thus, an anterior ocular condition can include a disease, ailment orcondition, such as for example, aphakia; pseudophakia; astigmatism;blepharospasm; cataract; conjunctival diseases; conjunctivitis; cornealdiseases; corneal ulcer; dry eye syndromes; eyelid diseases; lacrimalapparatus diseases; lacrimal duct obstruction; myopia; presbyopia; pupildisorders; refractive disorders and strabismus. Glaucoma can also beconsidered to be an anterior ocular condition because a clinical goal ofglaucoma treatment can be to reduce a hypertension of aqueous fluid inthe anterior chamber of the eye (i.e. reduce intraocular pressure).

A posterior ocular condition is a disease, ailment or condition whichprimarily affects or involves a posterior ocular region or site such aschoroid or sclera (in a position posterior to a plane through theposterior wall of the lens capsule), vitreous, vitreous chamber, retina,optic nerve (i.e. the optic disc), and blood vessels and nerves whichvascularize or innervate a posterior ocular region or site.

Thus, a posterior ocular condition can include a disease, ailment orcondition, such as for example, acute macular neuroretinopathy; Behcet'sdisease; choroidal neovascularization; diabetic uveitis; histoplasmosis;infections, such as fungal or viral-caused infections; maculardegeneration, such as acute macular degeneration, non-exudative agerelated macular degeneration and exudative age related maculardegeneration; edema, such as macular edema, cystoid macular edema anddiabetic macular edema; multifocal choroiditis; ocular trauma whichaffects a posterior ocular site or location; ocular tumors; retinaldisorders, such as central retinal vein occlusion, diabetic retinopathy(including proliferative diabetic retinopathy), proliferativevitreoretinopathy (PVR), retinal arterial occlusive disease, retinaldetachment, uveitic retinal disease; sympathetic ophthalmia; VogtKoyanagi-Harada (VKH) syndrome; uveal diffusion; a posterior ocularcondition caused by or influenced by an ocular laser treatment;posterior ocular conditions caused by or influenced by a photodynamictherapy, photocoagulation, radiation retinopathy, epiretinal membranedisorders, branch retinal vein occlusion, anterior ischemic opticneuropathy, non-retinopathy diabetic retinal dysfunction, retinitispigmentosa, and glaucoma. Glaucoma can be considered a posterior ocularcondition because the therapeutic goal is to prevent the loss of orreduce the occurrence of loss of vision due to damage to or loss ofretinal cells or optic nerve cells (i.e. neuroprotection).

The term “biodegradable polymer” refers to a polymer or polymers whichdegrade in vivo, and wherein erosion of the polymer or polymers overtime occurs concurrently with or subsequent to release of thetherapeutic agent. Specifically, hydrogels such as methylcellulose whichact to release drug through polymer swelling are specifically excludedfrom the term “biodegradable polymer”. The terms “biodegradable” and“bioerodible” are equivalent and are used interchangeably herein. Abiodegradable polymer may be a homopolymer, a copolymer, or a polymercomprising more than two different polymeric units.

The term “treat”, “treating”, or “treatment” as used herein, refers toreduction or resolution or prevention of an ocular condition, ocularinjury or damage, or to promote healing of injured or damaged oculartissue.

The term “therapeutically effective amount” as used herein, refers tothe level or amount of agent needed to treat an ocular condition, orreduce or prevent ocular injury or damage without causing significantnegative or adverse side effects to the eye or a region of the eye.

Intraocular implants have been developed which can release drug loadsover various' time periods. These implants, which when inserted into aneye, such as the vitreous of an eye, provide therapeutic levels of asteroid for extended periods of time (e.g., for about 2 months or more).The implants disclosed are effective in treating ocular conditions, suchas posterior ocular conditions.

In one embodiment of the present invention, an intraocular implantcomprises a biodegradable polymer matrix. The biodegradable polymermatrix is one type of a drug release sustaining component. Thebiodegradable polymer matrix is effective in forming a biodegradableintraocular implant. The biodegradable intraocular implant comprises asteroid associated with the biodegradable polymer matrix. The matrixdegrades at a rate effective to sustain release of a therapeuticallyeffective amount of the steroid for a time greater than about two monthsfrom the time in which the implant is placed in ocular region or ocularsite, such as the vitreous of an eye.

The steroid of the implant may be a corticosteroid. In certainembodiments, the steroid may be a fluocinolone, a triamcinolone, or amixture of fluocinolone and triamcinolone. In some embodiments, thefluocinolone is provided in the implant as fluocinolone acetonide, andthe triamcinolone is provided in the implant as triamcinolone acetonide.Triamcinolone acetonide is publicly available under the tradename,KENALOG®. Another steroid useful in the present implants isbeclomethasone or beclomethasone dipropionate. Thus, the presentimplants may comprise one or more of the following: fluocinolone,fluocinolone acetonide, triamcinolone, triamcinolone acetonide,beclomethasone, or beclomethasone dipropionate.

The steroid may be in a particulate or powder form and entrapped by thebiodegradable polymer matrix. Usually, steroid particles will have aneffective average size less than about 3000 nanometers. In certainimplants, the particles may have an effective average particle sizeabout an order of magnitude smaller than 3000 nanometers. For example,the particles may have an effective average particle size of less thanabout 500 nanometers. In additional implants, the particles may have aneffective average particle size of less than about 400 nanometers, andin still further embodiments, a size less than about 200 nanometers.

The steroid of the implant is preferably from about 10 to 90% by weightof the implant. More preferably, the steroid is from about 50 to about80% by weight of the implant. In a preferred embodiment, the steroidcomprises about 50% by weight of the implant. In another embodiment, thesteroid comprises about 70% by weight of the implant.

Suitable polymeric materials or compositions for use in the implantinclude those materials which are compatible, that is biocompatible,with the eye so as to cause no substantial interference with thefunctioning or physiology of the eye. Such materials preferably are atleast partially and more preferably substantially completelybiodegradable or bioerodible.

Examples of useful polymeric materials include, without limitation, suchmaterials derived from and/or including organic esters and organicethers, which when degraded result in physiologically acceptabledegradation products, including the monomers. Also, polymeric materialsderived from and/or including, anhydrides, amides, orthoesters and thelike, by themselves or in combination with other monomers, may also finduse. The polymeric materials may be addition or condensation polymers,advantageously condensation polymers. The polymeric materials may becross-linked or non-cross-linked, for example not more than lightlycross-linked, such as less than about 5%, or less than about 1% of thepolymeric material being cross-linked. For the most part, besides carbonand hydrogen, the polymers will include at least one of oxygen andnitrogen, advantageously oxygen. The oxygen may be present as oxy, e.g.hydroxy or ether, carbonyl, e.g. non-oxo-carbonyl, such as carboxylicacid ester, and the like. The nitrogen may be present as amide, cyanoand amino. The polymers set forth in Heller, Biodegradable Polymers inControlled Drug Delivery, In: CRC Critical Reviews in Therapeutic DrugCarrier Systems, Vol. 1, CRC Press, Boca Raton, Fla. 1987, pp 39-90,which describes encapsulation for controlled drug delivery, may find usein the present implants.

Of additional interest are polymers of hydroxyaliphatic carboxylicacids, either homopolymers or copolymers, and polysaccharides.Polyesters of interest include polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. Generally, by employing the L-lactate or D-lactate, a slowlyeroding polymer or polymeric material is achieved, while erosion issubstantially enhanced with the lactate racemate.

Among the useful polysaccharides are, without limitation, calciumalginate, and functionalized celluloses, particularlycarboxymethylcellulose esters characterized by being water insoluble, amolecular weight of about 5 kD to 500 kD, for example.

Other polymers of interest include, without limitation, polyvinylalcohol, polyesters, polyethers and combinations thereof which arebiocompatible and may be biodegradable and/or bioerodible.

Some preferred characteristics of the polymers or polymeric materialsfor use in the present invention may include biocompatibility,compatibility with the therapeutic component, ease of use of the polymerin making the drug delivery systems of the present invention, ahalf-life in the physiological environment of at least about 6 hours,preferably greater than about one day, not significantly increasing theviscosity of the vitreous, and water insolubility.

The biodegradable polymeric materials which are included to form thematrix are desirably subject to enzymatic or hydrolytic instability.Water soluble polymers may be cross-linked with hydrolytic orbiodegradable unstable cross-links to provide useful water insolublepolymers. The degree of stability can be varied widely, depending uponthe choice of monomer, whether a homopolymer or copolymer is employed,employing mixtures of polymers, and whether the polymer includesterminal acid groups.

Equally important to controlling the biodegradation of the polymer andhence the extended release profile of the implant is the relativeaverage molecular weight of the polymeric composition employed in theimplant. Different molecular weights of the same or different polymericcompositions may be included in the implant to modulate the releaseprofile. In certain implants, the relative average molecular weight ofthe polymer will range from about 9 to about 60 kD, usually from about10 to about 54 kD, more usually from about 12 to about 45 kD, and mostusually less than about 40 kD.

In some implants, copolymers of glycolic acid and lactic acid are used,where the rate of biodegradation is controlled by the ratio of glycolicacid to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic acid and lactic acid. Homopolymers, orcopolymers having ratios other than equal, are more resistant todegradation. The ratio of glycolic acid to lactic acid will also affectthe brittleness of the implant, where a more flexible implant isdesirable for larger geometries. The % of polylactic acid in thepolylactic acid polyglycolic acid (PLGA) copolymer can be 0-100%,preferably about 15-85%, more preferably about 35-65%. In some implants,a 50/50 PLGA copolymer is used.

The biodegradable polymer matrix of the intraocular implant may comprisea mixture of two or more biodegradable polymers. For example, theimplant may comprise a mixture of a first biodegradable polymer and adifferent second biodegradable polymer. One or more of the biodegradablepolymers may have terminal acid groups. In certain implants, the matrixcomprises a first biodegradable polymer having terminal acid groups, anda different second biodegradable polymer having terminal acid groups.The first biodegradable polymer may be a poly(D,L-lactide-co-glycolide).The second biodegradable polymer may be a poly(D,L-lactide).

Release of a drug from an erodible polymer is the consequence of severalmechanisms or combinations of mechanisms. Some of these mechanismsinclude desorption from the implants surface, dissolution, diffusionthrough porous channels of the hydrated polymer and erosion. Erosion canbe bulk or surface or a combination of both. As discussed herein, thematrix of the intraocular implant may release drug at a rate effectiveto sustain release of a therapeutically effective amount of the steroidfor more than three months after implantation into an eye. In certainimplants, therapeutic amounts of the steroid are released for more thanfour months after implantation. For example, an implant may comprisefluocinolone, and the matrix of the implant degrades at a rate effectiveto sustain release of a therapeutically effective amount of fluocinolonefor about three months after being placed in an eye. As another example,the implant may comprise triamcinolone, and the matrix releases drug ata rate effective to sustain release of a therapeutically effectiveamount of triamcinolone for more than three months, such as from aboutthree months to about six months.

Release of a drug from the present implants can also be related to theamount of a drug present in the implant and the properties of thepolymers of the implant, such as polymer molecular weight and ratio ofglycolic acid to lactic acid. In one embodiment of the present implants,the drug, such as the steroid, is released at a first rate for a firsttime period that is substantially independent of the polymer properties,and the drug is released at a second rate for a second time period afterthe first time period that is dependent on the polymer properties of theimplant. For example, an implant comprises a steroid and a polymericcomponent that releases the steroid from the implant for a time periodof about thirty days primarily due to steroid dissolution, and releasesthe steroid from the implant after thirty days primarily due to polymerproperties.

One example of the biodegradable intraocular implant comprises a steroidassociated with a biodegradable polymer matrix, which comprises amixture of different biodegradable polymers. At least one of thebiodegradable polymers is a polylactide having a molecular weight lessthan 40 kD. Such a mixture is effective in sustaining release of atherapeutically effective amount of the steroid for a time periodgreater than about two months from the time the implant is placed in aneye. In certain embodiments, the polylactide has a molecular weight lessthan 20 kD. In other embodiments, the polylactide has a molecular weightof about 10 kD. The polylactide may be a poly(D,L-lactide), and thepolylactide may include polymers having terminal free acid groups. Inone particular embodiment, the matrix of the implant comprises a mixtureof poly(lactide-co-glycolide) and polylactide. Each of thepoly(lactide-co-glycolide) and polylactide may have terminal free acidgroups.

Another example of a biodegradable intraocular implant comprises asteroid associated with a biodegradable polymer matrix, which comprisesa mixture of different biodegradable polymers, each biodegradablepolymer having an inherent viscosity from about 0.16 dl/g to about 0.24dl/g. For example, one of the biodegradable polymers may have aninherent viscosity of about 0.2 dl/g. Or, the mixture may comprise twodifferent biodegradable polymers, and each of the biodegradable polymershas an inherent viscosity of about 0.2 dl/g. The inherent viscositiesidentified above may be determined in 0.1% chloroform at 25° C.

Other implants may include a biodegradable polymer matrix ofbiodegradable polymers, at least one of the polymers having an inherentviscosity of about 0.25 dl/g to about 0.35 dl/g. Additional implants maycomprise a mixture of biodegradable polymers wherein each polymer has aninherent viscosity from about 0.50 dl/g to about 0.70 dl/g.

The release of the steroid from the intraocular implant comprising abiodegradable polymer matrix may include an initial burst of releasefollowed by a gradual increase in the amount of the steroid released, orthe release may include an initial delay in release of the steroidfollowed by an increase in release. When the implant is substantiallycompletely degraded, the percent of the steroid that has been releasedis about one hundred. Compared to existing implants, the implantsdisclosed herein do not completely release, or release about 100% of thesteroid, until after about two months of being placed in an eye. Thus,the implants exhibit a cumulative release profile that may have ashallower slope, or a lower rate of release, for longer periods of timethan existing implants.

In at least one embodiment, the present implants release the steroidinto the interior of the eye in an amount having a reduced toxicityrelative to bolus or liquid injections of the same steroid without apolymeric component. For example, it has been reported that a single orrepeated 20 mg dose of Kenalog 40 results in substantial retinalchanges, including changes in the retinal pigment epithelium. Such dosesmay be necessary in liquid formulations to provide prolonged therapeuticeffects.

In comparison, the present implants can provide therapeuticallyeffective amounts of the steroid for prolonged periods of time withoutrequiring such large doses. Thus, present implants may contain 1 mg, 2mg, 3 mg, 4 mg, or 5 mg of a steroid, such as triamcinolone acetonide orfluocinolone acetonide, the steroid is gradually released over timewithout causing substantial ocular toxicity or other adverse sideeffects that are associated with injection of 20 mg of the steroid in aliquid formulation. Thus, in one embodiment, an intravitreal implantcomprises triamcinolone acetonide and a biodegradable polymer associatedwith the triamcinolone acetonide in the form of an intravitreal implantthat releases the triamcinolone acetonide in amounts associated with areduced toxicity relative to the toxicity associated with administeringtriamcinolone acetonide in a liquid composition.

It may be desirable to provide a relatively constant rate of release ofthe steroid from the implant over the life of the implant. For example,it may be desirable for the steroid to be released in amounts from about0.01 μg to about 2 μg per day for the live of the implant. However, therelease rate may change to either increase or decrease depending on theformulation of the biodegradable polymer matrix. In addition, therelease profile of the steroid may include one or more linear portionsand/or one or more non-linear portions. Preferably, the release rate isgreater than zero once the implant has begun to degrade or erode.

The implants may be monolithic, i.e. having the active agent or agentshomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. Due to ease of manufacture, monolithic implants are usuallypreferred over encapsulated forms. However, the greater control affordedby the encapsulated, reservoir-type implant may be of benefit in somecircumstances, where the therapeutic level of the drug falls within anarrow window. In addition, the therapeutic component, including thesteroid, may be distributed in a non-homogenous pattern in the matrix.For example, the implant may include a portion that has a greaterconcentration of the steroid relative to a second portion of theimplant.

In another embodiment of the present invention, an intraocular implantcomprises a therapeutic component, including a steroid, and a drugrelease sustaining component including a coating covering a core regionof the implant. The therapeutic component is provided in the coreregion. The polymeric outer layer may be impermeable to the therapeuticcomponent and ocular fluids. Or, the polymeric outer layer may beinitially impermeable to the therapeutic component and ocular fluids,but then may become permeable to the therapeutic component or ocularfluids as the outer layer degrades. Thus, the polymeric outer layer maycomprise a polymer such as polytetrafluoroethylene, polyfluorinatedethylenepropylene, polylactic acid, polyglycolic acid, silicone, ormixtures thereof.

The foregoing implant may be understood to include a reservoir of one ormore therapeutic agents, such as a steroid. In certain implants, thesteroid may be a corticosteroid, such as fluocinolone or triamcinolone,as discussed above. One example of an implant including a reservoir of atherapeutic agent is described in U.S. Pat. No. 6,331,313.

In some implants, the drug release sustaining component comprises apolymeric outer layer covering the therapeutic component, the outerlayer comprises a plurality of openings or holes through which thetherapeutic component may pass from the drug delivery system to anexternal environment of the implant, such as an ocular region of an eye.The holes enable a liquid to enter into the interior of the implant anddissolve the therapeutic agent contained therein. The release of thetherapeutic agent from the implant may be influenced by the drugsolubility in the liquid, the size of the hole(s), and the number ofholes. In certain implants, the hole size and number of holes areeffective in providing substantially all of the desired releasecharacteristics of the implant. Thus, additional excipients may not benecessary to achieve the desired results. However, in other implants,excipients may be provided to further augment the releasecharacteristics of the implant.

Various biocompatible substantially impermeable polymeric compositionsmay be employed in preparing the outer layer of the implant. Somerelevant factors to be considered in choosing a polymeric compositioninclude: compatibility of the polymer with the biological environment ofthe implant, compatibility of the drug with the polymer, ease ofmanufacture, a half-life in the physiological environment of at leastseveral days, no significant enhancement of the viscosity of thevitreous, and the desired rate of release of the drug. Depending on therelative importance of these characteristics, the compositions can bevaried. Several such polymers and their methods of preparation arewell-known in the art. See, for example, U.S. Pat. Nos. 4,304,765;4,668,506 4,959,217; 4,144,317, and 5,824,074, Encyclopedia of PolymerScience and Technology, Vol. 3, published by Interscience Publishers,Inc., New York, latest edition, and Handbook of Common Polymers byScott, J. R. and Roff, W. J., published by CRC Press, Cleveland, Ohio,latest edition.

The polymers of interest may be homopolymers, copolymers, straight,branched-chain, or cross-linked derivatives. Some exemplary polymersinclude: polycarbamates or polyureas, cross-linked poly(vinyl acetate)and the like, ethylene-vinyl ester copolymers having an ester content of4 to 80% such as ethylene-vinyl acetate (EVA) copolymer, ethylene-vinylhexanoate copolymer, ethylene-vinyl propionate copolymer, ethylene-vinylbutyrate copolymer, ethylene-vinyl pentanoate copolymer, ethylene-vinyltrimethyl acetate copolymer, ethylene-vinyl diethyl acetate copolymer,ethylene-vinyl 3-methyl butanoate copolymer, ethylene-vinyl 3-3-dimethylbutanoate copolymer, and ethylene-vinyl benzoate copolymer, or mixturesthereof.

Additional examples include polymers such as: poly(methylmethacrylate),poly(butylmethacrylate), plasticized poly(vinylchloride), plasticizedpoly(amides), plasticized nylon, plasticized soft nylon, plasticizedpoly(ethylene terephthalate), natural rubber, silicone, poly(isoprene),poly(isobutylene), poly(butadiene), poly(ethylene),poly(tetrafluoroethylene), poly(vinylidene chloride),poly(acrylonitrile, cross-linked poly(vinylpyrrolidone), chlorinatedpoly(ethylene), poly(trifluorochloroethylene), poly(ethylenechlorotrifluoroethylene), poly(tetrafluoroethylene), poly(ethylenetetrafluoroethylene), poly(4,4′-isopropylidene diphenylene carbonate),polyurethane, poly(perfluoroalkoxy), poly(vinylidenefluoride),vinylidene chloride-acrylonitrile copolymer, vinyl chloride-diethylfumarate copolymer, silicone, silicone rubbers (of medical grade such asSilastic® Medical Grade ETR Elastomer Q7-4750 or Dow Corning® MDX 4-4210Medical Grade Elastomer); and cross-linked copolymers ofpolydimethylsilane silicone polymers.

Some further examples of polymers include: poly(dimethylsiloxanes),ethylene-propylene rubber, silicone-carbonate copolymers, vinylidenechloride-vinyl chloride copolymer, vinyl chloride-acrylonitrilecopolymer, vinylidene chloride-acrylonitrile copolymer, poly(olefins),poly(vinyl-olefins), poly(styrene), poly(halo-olefins), poly(vinyls)such as polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linkedpolyvinyl butyrate, ethylene ethylacrylate copolymer, polyethylhexylacrylate, polyvinyl chloride, polyvinyl acetals, plasticizedethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate,ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate,polyvinylformal, poly(acrylate), poly(methacrylate), poly(oxides),poly(esters), poly(amides), and poly(carbonates), or mixtures thereof.

In some aspects, the implants with an outer layer coating with holes maybe biodegradable wherein the outer layer degrades after the drug hasbeen released for the desired duration. The biodegradable polymericcompositions may comprise any of the above-identified biodegradablepolymers or combinations thereof. In some implants, the polymer ispolytetrafluoroethylene, (commercially known as Teflon®), ethyl vinylalcohol or ethylene vinyl acetate.

The steroid containing implants typically exhibited desirable releasetimes with orifices configured to have a total area of less than 1% ofthe total surface area of the implant. A substantially cylindricallyshaped implant has a first end, a second end, and a body portion betweenthe first end and the second end. Typically, the implants disclosedherein are sealed at the first and second ends. One or more holes areformed in the body portion of the implant. The holes typically have adiameter of at least about 250 μm and less than about 500 μm. Forexample, holes may have a diameter of about 250 μm, 325 μm, 375 μm, or500 μm. Smaller holes may be provided in other implants. Typically, twoor three holes are provided in the implant outer layer. The holes may bespaced apart by a distance from about 1 mm to about 2 mm for implantshaving a length of about 7 mm to about 10 mm.

In one steroid-containing implant, the total area of the holes was about0.311% of the total surface area of the implant. In anothersteroid-containing implant, the total area of the holes was about 0.9%of the total surface area of the implant. The area of an orifice or holeis determined by the following formula:Area=3.1416×r ²where r is the radius of the orifice. The area for each orifice may bedetermined and added together to determine the total orifice area. Thetubular implant surface area may be determined by the following formula:Surface area=3.1416×OD×length+2×3.1416r _(od) ²where OD is the outer diameter of a cross-section of the tubularimplant, length is the length of the tubular implant, and r_(od) is theradius of the cross-section of the tubular implant.

In the configurations described above, the implant is capable ofreleasing the steroid at concentrations less than 2 μg/day. Someimplants were capable of releasing the steroid at a concentration ofabout 0.5 μg/day. These implants are capable of providingtherapeutically effective amounts of the steroid to an ocular region ofan eye for more than one year, such as for more than five years, andeven for about 13 years.

Examples of materials used and methods of making such implants aredisclosed in U.S. Pat. No. 6,331,313. Briefly, a coating is formedaround a core containing a therapeutic agent. The core may include atherapeutic agent associated with a biodegradable polymer matrix, or thecore may be formed by filling a preformed coating, such as a tube.

The therapeutic agent can be deposited in a preformed coating as a drypowder, particles, granules, or as a compressed solid. The therapeuticagent may also be present in a solution. In addition, the core cancomprise a mixture of a biodegradable polymer matrix and the therapeuticagent, such as the matrix containing implants described above. Thepolymers used in the matrix with the therapeutic agent arebio-compatible with body tissues and body fluids and can bebiodegradable or substantially insoluble in the body fluids. Any of theabove-described biocompatible polymer compositions can be used toprepare the matrix. The amount of polymer in the core may be from about0% to 80 wt % by weight. These polymers are commercially available andmethods for preparing polymer matrices are well-known in the art. See,for example, U.S. Pat. No. 5,882,682.

The biocompatible, substantially impermeable outer layer can be obtainedby coating the core with a polymeric composition described above. Thecoat can be applied using organic solvents, and the solvents may then bevacuum stripped from the coat to leave a dry coat. The polymer, at aconcentration of from about 10 to about 80 weight percent is dissolvedor suspended in an organic solvent at the appropriate temperature, forexample for polylactic polymer, between 60 degrees to 90 degrees C. Theresulting mixture can be cut, molded, injection molded, extruded, orpoured or sprayed onto a pre-formed core into any shape or size forimplantation. The spraying can be accomplished in a rotating pan coateror in a fluidized bed coater until the desired coating thickness isachieved.

Alternatively, the core may be dip coated or melt coated. This type ofcoating is especially useful with waxes and oils. In another embodiment,the core may be compression coated, wherein a suitable polymericcomposition may be pressed onto a preformed core. In another aspect, anadhesive coat such as shellac or polyvinyl acetate phthalate (PVAP) isapplied to the core prior to applying the impermeable coating in orderto improve adhesion of the impermeable coating to the core. Thesetechniques are well-known in the art. See, for example, Handbook ofCommon Polymers, by J. R. Scott and W. J. Roff, Section 64, (1971)published by CRC Press, Cleveland, Ohio.

When the outer layer is injection molded or extruded into the desiredshape, the cavity formed by the outer layer can be then filled with thetherapeutic agent composition. Then, the ends are sealed with an endcap. At least one orifice is drilled in the device. Optionally, anorifice is drilled, or preformed in the wall, or an orifice is sealedwith a break-off tab that is broken open, or cut open, or the like, atthe time of use.

Alternatively, the core-free device may be loaded with therapeutic agentby, for example, immersing the device in a solution comprising thetherapeutic agent for a time sufficient for absorption of thetherapeutic agent. The device may be equipped with a hollow fiber andthe therapeutic agent may be directly loaded into the fiber and thedevice subsequently sealed. Where the activity of the therapeutic agentwill not be compromised, the therapeutic agent-filled device may then bedried or partially dried for storage until use. This method may findparticular application where the activity of the therapeutic agent ofchoice is sensitive to exposure to solvents, heat or other aspects ofthe conventional solvent-evaporation, molding, extrusion or othermethods described above.

The orifice may be formed using any technique known in the art. Forinstance, the orifice may be made using a needle or other form of boringinstrument such as a mechanical drill or a laser to remove a section ofthe impermeable portion of the device. Alternatively, a speciallydesigned punch tip may be incorporated into the compressing equipment,in order to pierce through the impermeable portion at the point ofcompaction.

The holes may be made by drilling the appropriate size hole through awall of the device using a mechanical or laser-based process. In someimplants, a digital laser marking system is used to drill the holes.This system allows for an array of apertures to be drilled on both facesof a dosage form simultaneously and at rates suitable for production ofdosage forms. The process utilizes a digital laser marking system (forexample the DigiMark™ variable marking system, available from DirectedEnergy, Inc.) to produce an unlimited number of holes through thesurface or coating of the dosage form, at rates practically suitable forproduction of dosage forms.

The steps involved in this laser drilling process are as follows: adigital laser marking system is focused at a laser stage; the dosageform is moved onto the laser stage of the digital laser marking systemis pulsed to energize those laser tubes needed to drill the desiredapertures along a linear array on the dosage form, the dosage form ismoved forward on the laser stage and the digital laser marking system isagain pulsed as needed to produce an additional linear array ofapertures; the dosage form is then removed from the laser stage.

Orifices and equipment for forming orifices are disclosed in U.S. Pat.Nos. 3,845,770; 3,916,899; 4,063,064 and 4,008,864. Orifices formed byleaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987. Laserdrilling machines equipped with photo wave length detecting systems fororienting a device are described in U.S. Pat. No. 4,063,064 and in U.S.Pat. No. 4,088,864.

The intraocular implants disclosed herein may have a size of betweenabout 5 μm and about 10 mm, or between about 10 μm and about 1 mm foradministration with a needle, greater than 1 mm, or greater than 2 mm,such as 3 mm or up to 10 mm, for administration by surgicalimplantation. For needle-injected implants, the implants may have anyappropriate length so long as the diameter of the implant permits theimplant to move through a needle. For example, implants having a lengthof about 6 mm to about 7 mm have been injected into an eye. The implantsadministered by way of a needle should have a diameter that is less thanthe inner diameter of the needle. In certain implants, the diameter isless than about 500 μm. The vitreous chamber in humans is able toaccommodate relatively large implants of varying geometries, havinglengths of, for example, 1 to 10 mm. The implant may be a cylindricalpellet (e.g., rod) with dimensions of about 2 mm×0.75 mm diameter. Orthe implant may be a cylindrical pellet with a length of about 7 mm toabout 10 mm, and a diameter of about 0.75 mm to about 1.5 mm.

The implants may also be at least somewhat flexible so as to facilitateboth insertion of the implant in the eye, such as in the vitreous, andaccommodation of the implant. The total weight of the implant is usuallyabout 250-5000 μg, more preferably about 500-1000 μg. For example, animplant may be about 500 μg, or about 1000 μg. For non-humanindividuals, the dimensions and total weight of the implant(s) may belarger or smaller, depending on the type of individual. For example,humans have a vitreous volume of approximately 3.8 ml, compared withapproximately 30 ml for horses, and approximately 60-100 ml forelephants. An implant sized for use in a human may be scaled up or downaccordingly for other animals, for example, about 8 times larger for animplant for a horse, or about, for example, 26 times larger for animplant for an elephant.

Thus, implants can be prepared where the center may be of one materialand the surface may have one or more layers of the same or a differentcomposition, where the layers may be cross-linked, or of a differentmolecular weight, different density or porosity, or the like. Forexample, where it is desirable to quickly release an initial bolus ofdrug, the center may be a polylactate coated with apolylactate-polyglycolate copolymer, so as to enhance the rate ofinitial degradation. Alternatively, the center may be polyvinyl alcoholcoated with polylactate, so that upon degradation of the polylactateexterior the center would dissolve and be rapidly washed out of the eye.

The implants, particularly the implants with the steroid associated witha biodegradable polymer matrix, may be of any geometry including fibers,sheets, films, microspheres, spheres, circular discs, plaques and thelike. The upper limit for the implant size will be determined by factorssuch as toleration for the implant, size limitations on insertion, easeof handling, etc. Where sheets or films are employed, the sheets orfilms will be in the range of at least about 0.5 mm×0.5 mm, usuallyabout 3-10 mm×5-10 mm with a thickness of about 0.1-1.0 mm for ease ofhandling. Where fibers are employed, the fiber diameter will generallybe in the range of about 0.05 to 3 mm and the fiber length willgenerally be in the range of about 0.5-10 mm. Spheres may be in therange of about 0.5 μm to 4 mm in diameter, with comparable volumes forother shaped particles.

The size and form of the implant can also be used to control the rate ofrelease, period of treatment, and drug concentration at the site ofimplantation. Larger implants will deliver a proportionately largerdose, but depending on the surface to mass ratio, may have a slowerrelease rate. The particular size and geometry of the implant are chosento suit the site of implantation.

The proportions of steroid, polymer, and any other modifiers may beempirically determined by formulating several implants with varyingproportions. A USP approved method for dissolution or release test canbe used to measure the rate of release (USP 23; NF 18 (1995) pp.1790-1798). For example, using the infinite sink method, a weighedsample of the implant is added to a measured volume of a solutioncontaining 0.9% NaCl in water, where the solution volume will be suchthat the drug concentration is after release is less than 5% ofsaturation. The mixture is maintained at 37° C. and stirred slowly tomaintain the implants in suspension. The appearance of the dissolveddrug as a function of time may be followed by various methods known inthe art, such as spectrophotometrically, HPLC, mass spectroscopy, etc.until the absorbance becomes constant or until greater than 90% of thedrug has been released.

In addition to the steroid or steroids included in the intraocularimplants disclosed herein, the intraocular implants may also include oneor more additional ophthalmically acceptable therapeutic agents. Forexample, the implant may include one or more antihistamines, one or moreantibiotics, one or more beta blockers, one or more differentcorticosteroids, one or more antineoplastic agents, one or moreimmunosuppressive agents, one or more antiviral agents, one or moreantioxidant agents, and mixtures thereof.

Pharmacologic or therapeutic agents which may find use in the presentsystems, include, without limitation, those disclosed in U.S. Pat. No.4,474,451, columns 4-6 and U.S. Pat. No. 4,327,725, columns 7-8.

Examples of antihistamines include, and are not limited to, loratadine,hydroxyzine, diphenhydramine, chlorpheniramine, brompheniramine,cyproheptadine, terfenadine, clemastine, triprolidine, carbinoxamine,diphenylpyraline, phenindamine, azatadine, tripelennamine,dexchlorpheniramine, dexbrompheniramine, methdilazine, and trimeprazinedoxylamine, pheniramine, pyrilamine, chlorcyclizine, thonzylamine, andderivatives thereof.

Examples of antibiotics include without limitation, cefazolin,cephradine, cefaclor, cephapirin, ceftizoxime, cefoperazone, cefotetan,cefuroxime, cefotaxime, cefadroxil, ceftazidime, cephalexin,cephalothin, cefamandole, cefoxitin, cefonicid, ceforanide, ceftriaxone,cefadroxil, cephradine, cefuroxime, ampicillin, amoxicillin,cyclacillin, ampicillin, penicillin G, penicillin V potassium,piperacillin, oxacillin, bacampicillin, cloxacillin, ticarcillin,azlocillin, carbenicillin, methicillin, nafcillin, erythromycin,tetracycline, doxycycline, minocycline, aztreonam, chloramphenicol,ciprofloxacin hydrochloride, clindamycin, metronidazole, gentamicin,lincomycin, tobramycin, vancomycin, polymyxin B sulfate, colistimethate,colistin, azithromycin, augmentin, sulfamethoxazole, trimethoprim, andderivatives thereof.

Examples of beta blockers include acebutolol, atenolol, labetalol,metoprolol, propranolol, timolol, and derivatives thereof.

Examples of other corticosteroids include cortisone, prednisolone,fluorometholone, dexamethasone, medrysone, loteprednol, fluazacort,hydrocortisone, prednisone, betamethasone, prednisone,methylprednisolone, triamcinolone hexacetonide, paramethasone acetate,diflorasone, fluocinonide, derivatives thereof, and mixtures thereof.

Examples of antineoplastic agents include adriamycin, cyclophosphamide,actinomycin, bleomycin, daunorubicin, doxorubicin, epirubicin,mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU),methyl-CCNU, cisplatin, etoposide, interferons, camptothecin andderivatives thereof, phenesterine, taxol and derivatives thereof,taxotere and derivatives thereof, vinblastine, vincristine, tamoxifen,etoposide, piposulfan, cyclophosphamide, and flutamide, and derivativesthereof.

Examples of immunosuppressive agents include cyclosporine, azathioprine,tacrolimus, and derivatives thereof.

Examples of antiviral agents include interferon gamma, zidovudine,amantadine hydrochloride, ribavirin, acyclovir, valciclovir,dideoxycytidine, phosphonoformic acid, ganciclovir, and derivativesthereof.

Examples of antioxidant agents include ascorbate, alpha-tocopherol,mannitol, reduced glutathione, various carotenoids, cysteine, uric acid,taurine, tyrosine, superoxide dismutase, lutein, zeaxanthin,cryptoxanthin, astaxanthin, lycopene, N-acetyl-cysteine, carnosine,gamma-glutamylcysteine, quercetin, lactoferrin, dihydrolipoic acid,citrate, Ginkgo Biloba extract, tea catechins, bilberry extract,vitamins E or esters of vitamin E, retinyl palmitate, and derivativesthereof.

Other therapeutic agents include squalamine, carbonic anhydraseinhibitors, alpha agonists, prostamides, prostaglandins, antiparasitics,antifungals, and derivatives thereof.

The amount of active agent or agents employed in the implant,individually or in combination, will vary widely depending on theeffective dosage required and the desired rate of release from theimplant. Usually the agent will be at least about 1, more usually atleast about 10 weight percent of the implant, and usually not more thanabout 80, more usually not more than about 40 weight percent of theimplant.

In addition to the therapeutic component, the intraocular implantsdisclosed herein may include effective amounts of buffering agents,preservatives and the like. Suitable water soluble buffering agentsinclude, without limitation, alkali and alkaline earth carbonates,phosphates, bicarbonates, citrates, borates, acetates, succinates andthe like, such as sodium phosphate, citrate, borate, acetate,bicarbonate, carbonate and the like. These agents advantageously presentin amounts sufficient to maintain a pH of the system of between about 2to about 9 and more preferably about 4 to about 8. As such the bufferingagent may be as much as about 5% by weight of the total implant.Suitable water soluble preservatives include sodium bisulfite, sodiumbisulfate, sodium thiosulfate, ascorbate, benzalkonium chloride,chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuricborate, phenylmercuric nitrate, parabens, methylparaben, polyvinylalcohol, benzyl alcohol, phenylethanol and the like and mixturesthereof. These agents may be present in amounts of from 0.001 to about5% by weight and preferably 0.01 to about 2% by weight.

In some situations mixtures of implants may be utilized employing thesame or different pharmacological agents. In this way, a cocktail ofrelease profiles, giving a biphasic or triphasic release with a singleadministration is achieved, where the pattern of release may be greatlyvaried.

Additionally, release modulators such as those described in U.S. Pat.No. 5,869,079 may be included in the implants. The amount of releasemodulator employed will be dependent on the desired release profile, theactivity of the modulator, and on the release profile of theglucocorticoid in the absence of modulator. Electrolytes such as sodiumchloride and potassium chloride may also be included in the implant.Where the buffering agent or enhancer is hydrophilic, it may also act asa release accelerator. Hydrophilic additives act to increase the releaserates through faster dissolution of the material surrounding the drugparticles, which increases the surface area of the drug exposed, therebyincreasing the rate of drug bioerosion. Similarly, a hydrophobicbuffering agent or enhancer dissolve more slowly, slowing the exposureof drug particles, and thereby slowing the rate of drug bioerosion.

Various techniques may be employed to produce the implants describedherein. Useful techniques include, but are not necessarily limited to,solvent evaporation methods, phase separation methods, interfacialmethods, molding methods, injection molding methods, extrusion methods,co-extrusion methods, carver press method, die cutting methods, heatcompression, combinations thereof and the like.

Specific methods are discussed in U.S. Pat. No. 4,997,652. Extrusionmethods may be used to avoid the need for solvents in manufacturing.When using extrusion methods, the polymer and drug are chosen so as tobe stable at the temperatures required for manufacturing, usually atleast about 85 degrees Celsius. Extrusion methods use temperatures ofabout 25 degrees C. to about 150 degrees C., more preferably about 65degrees C. to about 130 degrees C. An implant may be produced bybringing the temperature to about 60 degrees C. to about 150 degrees C.for drug/polymer mixing, such as about 130 degrees C., for a time periodof about 0 to 1 hour, 0 to 30 minutes, or 5-15 minutes. For example, atime period may be about 10 minutes, preferably about 0 to 5 min. Theimplants are then extruded at a temperature of about 60 degrees C. toabout 130 degrees C., such as about 75 degrees C.

In addition, the implant may be coextruded so that a coating is formedover a core region during the manufacture of the implant.

Compression methods may be used to make the implants, and typicallyyield implants with faster release rates than extrusion methods.Compression methods may use pressures of about 50-150 psi, morepreferably about 70-80 psi, even more preferably about 76 psi, and usetemperatures of about 0 degrees C. to about 115 degrees C., morepreferably about 25 degrees C.

The implants of the present invention may be inserted into the eye, forexample the vitreous chamber of the eye, by a variety of methods,including placement by forceps or by trocar following making a 2-3 mmincision in the sclera. The method of placement may influence thetherapeutic component or drug release kinetics. For example, deliveringthe implant with a trocar may result in placement of the implant deeperwithin the vitreous than placement by forceps, which may result in theimplant being closer to the edge of the vitreous. The location of theimplant may influence the concentration gradients of therapeuticcomponent or drug surrounding the element, and thus influence therelease rates (e.g., an element placed closer to the edge of thevitreous may result in a slower release rate).

Among the diseases/conditions which can be treated or addressed inaccordance with the present invention include, without limitation, thefollowing:

MACULOPATHIES/RETINAL DEGENERATION: Non-Exudative Age Related MacularDegeneration (ARMD), Exudative Age Related Macular Degeneration (ARM D),Choroidal Neovascularization, Diabetic Retinopathy, Acute MacularNeuroretinopathy, Central Serous Chorioretinopathy, Cystoid MacularEdema, Diabetic Macular Edema.

UVEITIS/RETINITIS/CHOROIDITIS: Acute Multifocal Placoid PigmentEpitheliopathy, Behcet's Disease, Birdshot Retinochoroidopathy,Infectious (Syphilis, Lyme, Tuberculosis, Toxoplasmosis), IntermediateUveitis (Pars Planitis), Multifocal Choroiditis, Multiple EvanescentWhite Dot Syndrome (MEWDS), Ocular Sarcoidosis, Posterior Scleritis,Serpiginous Choroiditis, Subretinal Fibrosis and Uveitis Syndrome,Vogt-Koyanagi-Harada Syndrome.

VASCULAR DISEASES/EXUDATIVE DISEASES: Retinal Arterial OcclusiveDisease, Central Retinal Vein Occlusion, Disseminated IntravascularCoagulopathy, Branch Retinal Vein Occlusion, Hypertensive FundusChanges, Ocular Ischemic Syndrome, Retinal Arterial Microaneurysms,Coat's Disease, Parafoveal Telangiectasis, Hemi-Retinal Vein Occlusion,Papillophlebitis, Central Retinal Artery Occlusion, Branch RetinalArtery Occlusion, Carotid Artery Disease (CAD), Frosted Branch Angiitis,Sickle Cell Retinopathy and other Hemoglobinopathies, Angioid Streaks,Familial Exudative Vitreoretinopathy, Eales Disease.

TRAUMATIC/SURGICAL: Sympathetic Ophthalmia, Uveitic Retinal Disease,Retinal Detachment, Trauma, Laser, PDT, Photocoagulation, HypoperfusionDuring Surgery, Radiation Retinopathy, Bone Marrow TransplantRetinopathy.

PROLIFERATIVE DISORDERS: Proliferative Vitreal Retinopathy andEpiretinal Membranes, Proliferative Diabetic Retinopathy.

INFECTIOUS DISORDERS: Ocular Histoplasmosis, Ocular Toxocariasis,Presumed Ocular Histoplasmosis Syndrome (POHS), Endophthalmitis,Toxoplasmosis, Retinal Diseases Associated with HIV Infection, ChoroidalDisease Associated with HIV Infection, Uveitic Disease Associated withHIV Infection, Viral Retinitis, Acute Retinal Necrosis, ProgressiveOuter Retinal Necrosis, Fungal Retinal Diseases, Ocular Syphilis, OcularTuberculosis, Diffuse Unilateral Subacute Neuroretinitis, Myiasis.

GENETIC DISORDERS: Retinitis Pigmentosa, Systemic Disorders withAssociated Retinal Dystrophies, Congenital Stationary Night Blindness,Cone Dystrophies, Stargardt's Disease and Fundus Flavimaculatus, Best'sDisease, Pattern Dystrophy of the Retinal Pigmented Epithelium, X-LinkedRetinoschisis, Sorsby's Fundus Dystrophy, Benign Concentric Maculopathy,Bietti's Crystalline Dystrophy, pseudoxanthoma elasticum.

RETINAL TEARS/HOLES: Retinal Detachment, Macular Hole, Giant RetinalTear.

TUMORS: Retinal Disease Associated with Tumors, Congenital Hypertrophyof the RPE, Posterior Uveal Melanoma, Choroidal Hemangioma, ChoroidalOsteoma, Choroidal Metastasis, Combined Hamartoma of the Retina andRetinal Pigmented Epithelium, Retinoblastoma, Vasoproliferative Tumorsof the Ocular Fundus, Retinal Astrocytoma, Intraocular Lymphoid Tumors.

MISCELLANEOUS: Punctate Inner Choroidopathy, Acute Posterior MultifocalPlacoid Pigment Epitheliopathy, Myopic Retinal Degeneration, AcuteRetinal Pigment Epithelitis and the like.

In one embodiment, an implant, such as the implants disclosed herein, isadministered to a posterior segment of an eye of a human or animalpatient, and preferably, a living human or animal. In at least oneembodiment, an implant is administered without accessing the subretinalspace of the eye. For example, a method of treating a patient mayinclude placing the implant directly into the posterior chamber of theeye. In other embodiments, a method of treating a patient may compriseadministering an implant to the patient by at least one of intravitrealinjection, subconjunctival injection, sub-tenon injections, retrobulbarinjection, and suprachoroidal injection.

In at least one embodiment, a method of treating a posterior ocularcondition comprises administering one or more implants containing one ormore steroids, as disclosed herein to a patient by at least one ofintravitreal injection, subconjuctival injection, sub-tenon injection,retrobulbar injection, and suprachoroidal injection. A syringe apparatusincluding an appropriately sized needle, for example, a 22 guage needle,a 27 gauge needle or a 30 gauge needle, can be effectively used toinject the composition with the posterior segment of an eye of a humanor animal. Repeat injections are often not necessary due to the extendedrelease of the steroid from the implants.

The present implants provide prolonged therapy to patients in need ofocular therapy. As discussed herein, the present implants can release asteroid for at least about 2 months after placement in the vitreous ofan eye of a patient. In certain implants, the steroid, and/or othertherapeutic agents, can be released for at least about one year, forexample for about three years. In additional implants, the steroid canbe released at therapeutically effective amounts for more than threeyears, such as for about five years.

In another aspect of the invention, kits for treating an ocularcondition of the eye are provided, comprising: a) a container comprisingan extended release implant comprising a therapeutic component includinga steroid, such as fluocinolone or triamcinolone, and drug releasesustaining component; and b) instructions for use. Instructions mayinclude steps of how to handle the implants, how to insert the implantsinto an ocular region, and what to expect from using the implants.

In view of the disclosure herein, one embodiment of a biodegradableintraocular implant comprises a steroid, such as triamcinoloneacetonide, fluocinolone acetonide, dexamethasone, and the like, and abiodegradable polymeric component, and substantially no polyvinylalcohol. Such an implant may be useful in treating uveitis, includingnon-infectious uveitis, and other ocular disorders, including macularedema, age-related macular degeneration, and the disorders describedherein. Advantageously, these implants can be placed in the vitreous ofan eye of a patient, and can provide one or more therapeutic benefitswith relatively few or no side effects. For example, the steroid, suchas fluocinolone acetonide, can be released from the implant without thepatient developing cataracts, vitreous hemorrhage, retinalneovascularization, and/or ocular hypertension.

In another embodiment, the implant can comprise a steroid, such asfluocinolone acetonide, and the implant can have a form other than atablet. For example, the implant can be in the form of a rod, sphere,and the like. In certain implants, the implant is an extruded element ascompared to a compressed tablet. The implant may include an adhesivecomponent effective in retaining the implant in a fixed position in theeye. For example, certain implants, such as non-tablet implants, mayinclude a polyvinyl alcohol suture. Other implants, including compressedtablets, may include an adhesive component that is free of polyvinylalcohol. For example, a hydrogel material may be used to affix theimplant in the eye of a patient.

In a further embodiment, an implant can comprise a steroid, such asfluocinolone acetonide or triamcinolone acetonide, and an intraocularpressure reducing agent, such as an alpha-2 adrenergic agonist. Theseimplants may be particularly useful in preventing an increase inintraocular pressure associated with release of the steroid from theimplant into the eye.

In another embodiment, a steroid containing intraocular tablet maycomprise a polyvinyl alcohol coating over the tablet body, and besubstantially free of a silicone component. Some examples of usefulcoatings include those described above.

EXAMPLES

The following non-limiting examples provide those of ordinary skill inthe art with specific preferred drug delivery systems, methods of makingsuch systems, and methods to treat conditions within the scope of thepresent invention. The following examples are not intended to limit thescope of the invention.

Example 1 Manufacture and Testing of Implants Containing Fluocinoloneand a Biodegradable Polymer Matrix

Fluocinolone acetonide was combined with a polymer in a stainless steelmortar and mixed using the Turbula shaker set at 96 RPM for 15 minutes.The powder of the fluocinolone and polymer was scraped off the walls ofthe steel mortar and then mixed again for an additional 15 minutes. Thepowder blend was heated at temperatures ranging from 110° C. to 160° C.,depending on the polymer used, for a total of 30 minutes, forming apolymer/drug melt. The melt was pelletized, then loaded into the barreland extruded into filaments, and finally the filaments were cut intoabout 0.5 mg or about 1 mg size implants. The implants had a weightrange from about 450 μg to about 550 μg, or from about 900 μg to about1100 μg. The 1 mg size implants had a length of about 2 mm and adiameter of about 0.72 mm.

Each implant was placed in a 20 ml screw cap vial with 10 ml of 0.9%saline. The vials were placed in a shaking water bath at 37° C. 9 mlaliquots were removed and replaced with equal volume of fresh media onday 1, 4, 7 and every week thereafter. The in-vitro release testing wasperformed on each lot of implants in six replicates.

The drug assays were performed by HPLC, consisting of a Waters 2690Separation Module (or 2696) and Waters 2996 Photodiode Array Detector. AVarian Microsorb-MV™ 100 Å C18 column was used for separation and thedetector was set at 254 nm. The mobile phase was (50:50)acetonitrile/0.005M sodium acetate (pH=4.0). The flow rate was 1.00ml/min and the total run time for was 6 minutes. The release rate wasdetermined by calculating the amount of drug released in a given volumeof medium over time in μg/day.

A total of 20 fluocinolone acetonide formulations were prepared, asshown in Table 1. The polymers used were Boehringer Ingelheim ResomersRG755, RG503, R202H, RG502H, and RG502. The inherent viscosities wereabout 0.6, 0.4, 0.2, 0.2, and 0.2 dl/g, respectively. The averagemolecular weights were 40000, 28300, 6500, 8400, and 11400 daltons,respectively.

TABLE 1 Fluocinolone Acetonide Formulations Formulation Lot FA (w/w)Polymer I.V. (dl/g) Melt T Extru T (core) Nozzle DDS Size 1 453-98A 40%RG755 0.6 160° C. 122° C. 380 μm 0.5 mg 2 453-98B 40% RG755 0.6 160° C.122° C. 720 μm 0.5 mg 3 453-99 20% RG755 0.6 160° C. 116° C. 720 μm 1 mg4 453-100 40% RG503 0.4 150° C. 116° C. 720 μm 0.5 mg 5 453-101 20%RG503 0.4 150° C. 106° C. 720 μm 1 mg 6 453-116 40% R202H 0.2 110° C.90° C. 720 μm 0.5 mg 7 453-117 40% RG752 0.2 110° C. 90° C. 720 μm 0.5mg 8 453-118 40% RG502H 0.2 110° C. 84° C. 720 μm 0.5 mg 9 453-119 40%RG502 0.2 110° C. 92° C. 720 μm 0.5 mg 10 453-120 40% (1:1) RG502H/R202H0.2 110° C. 85° C. 720 μm 0.5 mg 11 453-121 40% (1:1) RG502H/RG752 0.2110° C. 83° C. 720 μm 0.5 mg 12 453-128 60% (3:1) RG502H/R202H 0.2 110°C. 95° C. 720 μm 0.5 mg 13 453-129 60% (3:1) RG502H/RG752 0.2 110° C.101° C. 720 μm 0.5 mg 14 453-130 60% (3:1) RG502H/RG502 0.2 110° C. 101°C. 720 μm 0.5 mg 15 453-131 60% (1:1) RG502H/R202H 0.2 110° C. 101° C.720 μm 0.5 mg 16 453-137 40% (1:2) RG502H/R202H 0.2 110° C. 88° C. 720μm 1 mg 17 453-138 40% (1:2) RG502H/RG752 0.2 110° C. 85° C. 720 μm 1 mg18 453-139 40% (1:2) RG502H/RG502 0.2 120° C. 85° C. 720 μm 1 mg 19453-140 40% (1:2) RG502H/RG503 n.a. 120° C. 99° C. 720 μm 1 mg 20453-141 40% (1:2) RG502H/RG755 n.a. 120° C. 99° C. 720 μm 1 mg FA =Fluocinolone Acetonide I.V. = inherent viscosity Melt T = meltingtemperature Extru T = extrusion temperature Nozzle = nozzle diameter(μm) DDS size = drug delivery system size (i.e., the weight of anindividual implant)

Of the 20 formulations prepared, 16 were screened for release testing(formulations # 1-11 and 16-20). Initially, the release medium was 10 mLphosphate buffer-saline (PBS) with 1 mL replacement at each time point,but almost no release was observed up to three weeks. The release mediumwas subsequently changed to PBS with 9 mL replacement, but the releasewas inconsistent and with unacceptably high standard deviations.Finally, the release medium was switched to 0.9% saline with 9 mLreplacement at each time point. The release profiles are shown in FIGS.1 and 2.

Most of the fluocinolone acetonide formulations released the total drugload in approximately 2-3 months. Of the 16 formulations, 11formulations exhibited release for about two months. Of the 11formulations, 6 formulations exhibited release for about three months.

In particular, all formulations prepared with Resomer RG755 (453-98A,453-98B, and 453-99) and RG752 (453-117) showed almost no release afterday 4 and their release studies were stopped after 1 month.

Formulations prepared with RG503 (453-100 and 453-101) and RG502(453-119) showed a delay of 3-4 weeks before releasing 100% between day49 and day 56.

The formulation prepared with RG502H (453-118) appeared to be thefastest, on day 49.

The formulation prepared with a (1:1) mixture of RG502H and R202H led tothe longest release, up to 84 days.

Finally, the formulation prepared with a (1:1) mixture of RG502H andRG752 appeared to be slower than the one prepared with RG502H (453-118)at first, but eventually ended up having complete release at day 49.

Based on these data, it was concluded that a mixture of RG502H and otherpolymers with slower release will provide a formulation with longerrelease and relatively closer to zero-order kinetics. One formulationwith desirable release properties was a 1:2 mixture of RG502H and R202H,which led to a release of 94% of the fluocinolone after 84 days.

Example 2 Manufacture and Testing of Implants Containing Triamcinoloneand a Biodegradable Polymer Matrix

Triamcinolone acetonide was combined with a polymer in a stainless steelmortar and mixed using the Turbula shaker set at 96 RPM for 15 minutes.The powder of the fluocinolone and polymer was scraped off the walls ofthe steel mortar and then mixed again for an additional 15 minutes. Thepowder blend was heated at temperatures ranging from 110° C. to 160° C.,depending on the polymer used, for a total of 30 minutes, forming apolymer/drug melt. The melt was pelletized, then loaded into the barreland extruded into filaments, and finally the filaments were cut intoabout 0.5 mg or about 1 mg size implants. The implants had a weightrange from about 450 μg to about 550 μg, or from about 900 μg to about1100 μg. The 1 mg size implants had a length of about 2 mm and adiameter of about 0.72 mm.

The testing of the triamcinolone implants was performed as described inExample 1.

A total of 16 triamcinolone acetonide formulations were prepared, asshown in Table 2. The polymers used were Boehringer Ingelheim ResomersRG755, RG503, R202H, RG502H, and RG502. The inherent viscosities were0.6, 0.4, 0.2, 0.2, and 0.2 dl/g, respectively. The average molecularweights were 40000, 28300, 6500, 8400, and 11400 daltons, respectively.

TABLE 2 Triamcinolone Acetonide Formulations Formulation Lot TA (w/w)Polymer I.V. (dl/g) Melt T Extru T (core) Nozzle DDS Size 1 453-96 50%RG755 0.6 160° C. 122° C. 720 μm 1 mg 2 453-97 50% RG503 0.4 150° C.116° C. 720 μm 1 mg 3 453-112 50% RG502 0.2 110° C. 105° C. 720 μm 1 mg4 453-113 50% RG502H 0.2 110° C. 90° C. 720 μm 1 mg 5 453-114 50% RG7520.2 110° C. 95° C. 720 μm 1 mg 6 453-115 50% R202H 0.2 110° C. 96° C.720 μm 1 mg 7 453-122 50% (1:1) RG502H/RG752 0.2 110° C. 83° C. 720 μm 1mg 8 453-123 50% (1:1) RG502H/R202H 0.2 110° C. 85° C. 720 μm 1 mg 9453-125 60% (3:1) RG502H/RG502 0.2 110° C. 92° C. 720 μm 1 mg 10 453-12660% (3:1) RG502H/R202H 0.2 110° C. 92° C. 720 μm 1 mg 11 453-127 60%(3:1) RG502H/RG752 0.2 110° C. 95° C. 720 μm 1 mg 12 453-132 60% (1:1)RG502H/R202H 0.2 110° C. 108° C. 720 μm 1 mg 13 453-133 50% (1:1)RG502H/RG502 0.2 110° C. 99° C. 720 μm 1 mg 14 453-134 50% (1:1)RG502H/RG755 N/A 110° C. 110° C. 720 μm 1 mg 15 453-135 50% (1:1)RG502H/RG503 N/A 110° C. 110° C. 720 μm 1 mg 16 453-136 50% (3:1)RG502H/RG502 0.2 110° C. 88° C. 720 μm 1 mg TA = Triamcinolone AcetonideI.V. = inherent viscosity Melt T = melting temperature Extru T =extrusion temperature Nozzle = nozzle diameter (μm) DDS size = drugdelivery system size (i.e., the weight of an individual implant)

Of the 16 formulations prepared, 8 were screened for release testing(formulations # 1-8). The same problem was encountered with the releasemedium as that of fluocinolone. The release medium was switched to 0.9%saline with 9 mL replacement at each time point. The release profilesare shown in FIG. 3.

Certain triamcinolone acetonide formulations had release periods ofabout 4-6 months. Of the eight formulations, five formulations exhibited4 or more months of release, and two formulations exhibited release formore than 5 months.

Formulations prepared with RG755 (453-96), RG752 (453-114) and R202H(453-115) showed essentially zero to very slow release.

The formulation prepared with RG502H (453-113) had the fastest andperhaps smoothest release profile with minimal delay lasting close to 4months.

The formulation prepared with RG502 (453-112) showed an equally fastrelease of 4 months, but there was a 2-3 weeks lag time. The formulationprepared with RG503 (453-97) showed a release longer than 4 months, butit also had 4 weeks lag time.

Similar to the formulations in Example 1, the formulation prepared witha (1:1) mixture of RG502H and R202H lot (453-123) led to a desirablerelease profile approaching 5 to 6 months. This release profile was themost linear and the longest (>140 days).

Based on the data of Examples 1 and 2, polymer blends appeared toachieve a more desired controlled release rate relative to singlepolymers. Using a slow degrading poly(D,L-lactide), such as R202H, andmixing it with a fast degrading poly(D,L-lactide-co-glycolide), such asRG502H, is effective in controlling the release rate of bothfluocinolone and triamcinolone acetonide.

Example 3 Manufacture and In Vitro Testing of Implants ContainingFluocinolone and a Polymeric Coating

Silicone tubing (Specialty Silicone Fabricators, Inc, SSF-METN-755, P.N.OP-2) was cut to either 10 mm or 7 mm tubes to form an implant element.Holes of various sizes were drilled (Photomachining, Inc) in the cuttubes. The configuration of each tube was characterized by the number ofholes, the diameter of holes and the distance between the holes, as wellas the tube length and the sterility of the tube. Each drilled tube wasglued on one end with silicone adhesive (Nusil Silicone Technology,MED-1511), and dried for 72 hours at ambient temperature and then packedwith fluocinolone acetonide. Each of the 10 mm long tube contained 4 to5 mg of fluocinolone, while each of the 7 mm long tubes contained 2 to 3mg of fluocinolone. Finally, the other end of each tube was glued anddried for 72 hours. The implants did not include any additionalexcipients or release modifiers. A total of 30 different tubeconfigurations were tested and are described in Table 3.

TABLE 3 Fluocinolone Reservoir Delivery Technology ConfigurationsAverage Before or After Tube Number of Configuration Lot# #Hole/Diam/Distance Drug Load (μg) γ Sterilization Length Replicates 1257-172-1 2 hole - 250 μm - 2 mm 4526 (n = 3) BS 1 cm 3 2 257-172-4 2hole - 500 μm - 2 mm 4667 (n = 3) BS 1 cm 3 3 257-172-7 3 hole - 250μm - 2 mm 4508 (n = 3) BS 1 cm 3 4 257-172-10 3 hole - 500 μm - 2 mm4437 (n = 3) BS 1 cm 3 5 267-33-1 2 hole - 250 μm - 2 mm 4699 (n = 1) AS1 cm 1 6 267-33-2 3 hole - 250 μm - 2 mm 4536 (n = 1) AS 1 cm 1 7267-33-3 2 hole - 500 μm - 2 mm 4457 (n = 1) AS 1 cm 1 8 267-33-4 3hole - 500 μm - 2 mm 4214 (n = 1) AS 1 cm 1 9 267-140 2 hole - 375 μm -2 mm 5228 (n = 3) BS 1 cm 3 10 267-140 2 hole - 460 μm - 2 mm 4466 (n =3) BS 1 cm 3 11 267-140 3 hole - 325 μm - 2 mm 4867 (n = 3) BS 1 cm 3 12267-140 3 hole - 375 μm - 2 mm 4566 (n = 3) BS 1 cm 3 13 285-1AS 2hole - 375 μm - 2 mm 4663 (n = 3) AS 1 cm 3 14 285-1AS 2 hole - 460 μm -2 mm 4806 (n = 3) AS 1 cm 3 15 285-1AS 3 hole - 325 μm - 2 mm 5168 (n =3) AS 1 cm 3 16 285-1AS 3 hole - 375 μm - 2 mm 4981 (n = 3) AS 1 cm 3 17285-54 2 hole - 250 μm - 2 mm 2804 (n = 3) AS 0.7 cm 3 18 285-54 2hole - 500 μm - 2 mm 2428 (n = 3) AS 0.7 cm 3 19 285-54 3 hole - 375μm - 2 mm 3068 (n = 3) AS 0.7 cm 3 20 285-54 3 hole - 500 μm - 2 mm 2899(n = 3) AS 0.7 cm 3 21 285-126C 2 hole - 250 μm - 1 mm 2770 (n = 3) BS0.7 cm 3 22 285-126C 2 hole - 375 μm - 1 mm 2591 (n = 3) BS 0.7 cm 3 23285-126C 2 hole - 375 μm - 2 mm 3245 (n = 3) BS 0.7 cm 3 24 285-126C 2hole - 500 μm - 1 mm 2819 (n = 3) BS 0.7 cm 3 25 285-126C 3 hole - 500μm - 1.5 mm 2955 (n = 3) BS 0.7 cm 3 26 285-126D 2 hole - 250 μm - 1 mm2615 (n = 3) AS 0.7 cm 3 27 285-126D 2 hole - 375 μm - 1 mm 2970 (n = 3)AS 0.7 cm 3 28 285-126D 2 hole - 375 μm - 2 mm 2932 (n = 3) AS 0.7 cm 329 285-126D 2 hole - 500 μm - 1 mm 2619 (n = 3) AS 0.7 cm 3 30 285-126D3 hole - 500 μm - 1.5 mm 2498 (n = 3) AS 0.7 cm 3

Each of the 30 implants was placed into a 5 mL centrifuge vial with capcontaining 1 mL of phosphate buffer-saline, pH 7.4 (PBS) at 37° C. Totalreplacement with equal volume of fresh medium was performed on day 1, 4,7, 14, 28, and every week thereafter. Drug assay was performed on aWaters HPLC system, which included a 2690 (or 2696) Separation Module,and a 2996 Photodiode Array Detector. A Rainin C18, 4.6×100 mm columnwas used for separation and detector was set at 254 nm. The mobile phasewas (50:50) acetonitrile-0.005M NaOAc/HOAc, pH 4.0 with flow rate of 1mL/min and a total run time of 10 min per sample. Release rates weredetermined by calculating the amount of drug being released in a givenvolume of medium over time and expressed in μg/day. The release testingwas performed on all 30 configurations in three replicates, except forconfigurations # 5 to 8, for which only one sample of each was tested.

The implants studied varied in the number of holes (2 or 3), hole sizes(250, 325, 375, 460, or 500 μm), distance between the holes (1 mm, 1.5mm, or 2 mm), length of the implant (1 cm or 0.7 cm), and before orafter gamma sterilization, as presented in Table 3.

In general, all 30 implants exhibited an initial burst of drug releaseon the first day then tapered off to day 7 or later, and finallygradually settled into an equilibrium release range starting after day14. The first eight configurations were 1 cm in length with drug load ofapproximately 4.5 mg±0.2 mg in each device, as shown in Table 3.Configurations 1 through 4 were non-sterile, while configurations 5through 8 were sterile. The cumulative amount released (μg) as afunction of time and the amount of release (μg) per day as a function oftime are presented in FIGS. 4 through 7.

Configuration #1 (2 hole—250 μm), #2 (2 hole—500 μm), #3 (3 hole—250μm), and #4 (3 hole—500 μm) gave an average release of 0.63±0.23,1.72±0.52, 0.94±0.30, and 2.82 μg/day±0.41 μg/day, respectively from day14 to day 487. These results were compared to their sterilecounterparts, configuration #5, #6, #7, and #8, which gave an averagerelease of 0.88, 1.10, 2.48, and 2.84 μg/day, respectively from day 14to day 448. A good correlation between the number of holes in aconfiguration and its average daily release was observed for the firstfour configurations. For example, configuration #3 has 3 holes andconfiguration #1 has two holes of the same diameter as #3, andconfiguration #3 released 1½ times more fluocinolone per day thanconfiguration #1. Similar results were obtained with configuration #4and configuration #2.

In configuration #5 (2 hole—250 μm), #6 (2 hole—500 μm), #7 (3 hole—250μm), and #8 (3 hole—500 μm), we see approximately a three-fold increasein the release rates between configuration #7 and #5, and also betweenconfiguration #8 and #6. This was a two-fold increase comparing to thenon-sterile counterparts. Configuration # 5 (2 holes—250 μm) released anaverage of 1 μg/day, and configuration # 7 (2 holes—500 μm) released anaverage of 3 μg/day.

Configurations #9 (2 hole—375 μm), #10 (2 hole—460 μm), #11 (3 hole—325μm), and #12 (3 hole—375 μm) were made and were non-sterile, whileconfigurations 13 through 16 were the sterile counterparts. Thecumulative amount released (μg) as a function of time and the amount ofrelease (μg) per day as a function of time are presented in FIGS. 8through 11. Results from day 14 to day 397 showed an average release of1.02±0.25, 1.22±0.29, 1.06±0.21, and 1.50±0.39 μg/day for configurations9, 10, 11, and 12, respectively. Similarly, the data for configurations13, 14, 15, and 16, which were the sterile counterparts, showed anaverage release of 1.92±0.23, 2.29±0.33, 1.94±0.18, and 3.15±0.64μg/day, respectively. Each of the sterile configurations appeared to bereleasing twice as fast as its non-sterile counterpart.

Configuration # 13 (2 hole—375 μm-2 mm apart) exhibited an averagerelease of 1.92±0.23 μg/day from day 14 through day 376. Likewise,configuration #15 (3 hole—325 μm-2 mm apart) achieved an average releaseof 1.94±0.18 μg/day from day 14 through day 376. In the same period oftime, configurations # 14 and # 16 achieved an average release of 2.29μg±±0.33 μg/day and 3.15 μg±0.64 μg/day, respectively. Furthermore,configurations # 13 and #15 achieved a total release of 16.02%±0.78% and14.22%±1.13%, respectively, after 376 days. Based on the release rate,the predicted life span of configurations # 13 and #15 are 6.4 and 7.24years, respectively.

Implants were also manufactured to provide a fluocinolone release rateof about 0.5 μg/day. Tubular implants were manufactured to have a lengthof about 0.7 cm filled with approximately 2.8 mg±0.34 mg of drug and areidentified as configurations 17, 18, 19, and 20. The cumulative amountof fluocinolone released (μg) as a function of time and the amount ofrelease (μg) per day as a function of time are presented in FIGS. 12 and13, respectively.

The results showed an average release of 0.95±0.14, 1.71±0.55,1.93±0.56, and 2.76±0.27 μg/day, for configurations 17, 18, 19, and 20,respectively, from day 14 through day 329. Since the length of the tubefor configurations 17, 18, 19, and 20 was shortened from 1.0 cm to 0.7cm, approximately 0.15 cm of silicone tubing was removed from both ends.As a result, the holes became much closer to the end of the tube, to theextent that the glue almost touched the circumference of the holesduring preparation. It was not clear whether this affected the releaseprofiles. To circumvent this potential problem, configurations withholes much closer to each other toward the center and away from the endswere prepared.

The last ten configurations were 0.7 cm in length with drug load ofapproximately 2.69 mg±0.36 mg in each device. Configurations 21 through25 were pre-sterile, while configurations 26 through 30 were sterile.The cumulative amount released (μg) as a function of time and the amountof release (μg) per day as a function of time are presented in FIGS. 14through 17.

Results from day 14 to day 289 showed an average release of 1.01±0.23,1.76±0.57, 1.73±0.30, 3.0±1.26, and 3.32±1.06 μg/day for configurations21, 22, 23, 23, and 25, respectively. Similarly, the data forconfigurations 26, 27, 28, 29, and 30, which were the sterilecounterparts, showed an average release of 0.48±0.03, 0.85±0.09,0.82±0.08, 1.19±0.15, and 1.97±0.69 μg/day, respectively, from day 14through day 289. Configuration # 26 (2 holes—250 μm-1 mm apart) achievedan average release of 0.5 μg/day (e.g., 0.48±0.03 μg/day from day 14through day 289) and a total release of 5.76%±0.32% over 289 days orclose to 9½ months. Based on its release rate, it has a life span of13.75 years. In general, the non-sterile configurations areapproximately twice as fast as the sterile counterparts.

Example 4 Manufacture and In Vivo Testing of Intraocular ImplantsContaining Fluocinolone and a Polymer Coating

An in vivo study was conducted with an implant as shown by configuration# 29 in Example 3. The implant was manufactured as described in Example3. Configuration # 29 achieved an average release of 1.19±0.15 μg/day,and a total release of 14.28%±1.59% over 289 days when tested in vitro.

The in vivo study was conducted on four rabbits. Thefluocinolone-containing implants were surgically implanted into theposterior segment (i.e., the vitreous) of the right eye (OD) and lefteye (OS) of each rabbit. The aqueous humor (15-20 μL) and the vitreoushumor (150-200 μL) were withdrawn for the first two rabbits, while thesampling for the remaining two rabbits was determined by a samplingschedule wherein the sampling days were days 7, 14, 21, 40, and 60, 90,and 120. The results of the in vivo study are shown in Table 4.

TABLE 4 Fluocinolone acetonide Levels in Vitreous Humor of Rabbit EyesFluocinolone (ng/mL) Posterior Day Segment 7 14 21 40 60 90 120 8408D242.00 8408S 88.60 8399D 9.08 6.84 3.06 4.56 10.26 15.18 8399S 44.0074.20 85.80 83.60 75.60 44.00 8407D 105.80 87.20 135.80 68.60 57.208407S 16.64 6.78 14.92 6.62 3.46 8397D 44.00 42.20 32.40 24.20 8397S40.80 22.60 23.00 24.80 Average 95.92 50.87 45.71 42.40 50.61 36.0828.14 SD 102.68 47.16 47.13 2.26 50.19 29.46 19.49

The mean vitreous levels of fluocinolone were relatively higher in thefirst week and then remained at approximately between 30 and 50 ng/mLbeyond the second week. Fluocinolone acetonide was not detected at anytime point in the anterior chamber of all eyes.

Thus, by way of Examples 3 and 4, implants have been developed that candeliver fluocinolone at a substantially constant release rate of 2μg/day or 0.5 μg/day for extended periods of time (e.g., for over 1-2years).

Configuration # 29 (2 hole—500 μm-1 mm) was used in the in vivo studyand fluocinolone acetonide concentrations were measured between 0.026μg/mL to 0.096 μg/mL over 120 days in the vitreous, while essentially nolevel was found in the aqueous humor.

It was noticed that the release profiles differed depending on when theimplants were sterilized. For some configurations, the beforesterilization release rates are about twice as fast as the aftersterilization ones, and in other configurations, the reverse wasobserved. It is possible that sterilization may change the size of theholes in the implants. Two animals developed cataracts after day 120.

Example 5

Treatment of Uveitis with an Intraocular Implant Containing FluocinoloneAssociated with a Biodegradable Polymer Matrix.

A 48 year old female presents with posterior uveitis. She complains ofsensitivity to light and ocular pain. An implant containing 250 μg offluocinolone acetonide and 250 μg of a combination of biodegradablepolymers (R502H and R202H at a 1:2 ratio, as described above inExample 1) is placed in the vitreous of both of the woman's eyes using atrocar. After about 2 days, the woman begins to notice a decrease inocular pain and light sensitivity. She also notices a decreased blurringof vision, and a decrease in floaters. Substantial relief from theuveitis symptoms is obtained within about 7 days, and persists for aboutthree months.

Example 6

Treatment of Uveitis with an Intraocular Implant Containing FluocinoloneAssociated with a Polymeric Coating.

A 62 year old male presents with posterior uveitis. An implantcontaining 250 μg of fluocinolone acetonide with a polymeric coatinghaving two 500 μm diameter holes spaced 1 mm apart is implanted into thevitreous of both of the patient's eyes using a trocar. The patientreports a decrease in pain and improvement in vision within a week afterimplantation. The improvements persist for about two years. No cataractsdevelop over that time.

Example 7

Treatment of Macular Edema with a Steroid Containing IntraocularImplant.

A 53 year old male with macular edema is treated by injecting abiodegradable implant into the vitreous of each of the patient's eyesusing a syringe with a needle. The implants contain 500 μg offluocinolone acetonide and 500 μg of PLGA. The patient reports adecrease in pain and improvement in vision within a week afterimplantation. The improvements persist for about two years. No cataractsdevelop over that time.

Example 8

Treatment of Macular Degeneration with a Steroid Containing IntraocularImplant.

A 82 year old female diagnosed with macular degeneration in her righteye is treated by intravitreal placement of a biodegradable implantcontaining 600 μg of fluocinolone acetonide and 500 μg of PLGA. Theimplant is placed near the fovea without interfering with the patient'svision. Further ophthalmic diagnosis indicates that macular degenerationis suspended, and the patient does not perceive further vision lossassociated with macular degeneration. Throughout the treatment,intraocular pressure remains within acceptable limits.

Example 9 Effects of Polymer Properties and Drug Load on IntraocularImplants

This example describes effects of poly(lactide-co-glycolide) (PLGA)polymer properties and drug load on in-vitro drug release profiles ofsteroids from polymeric implants. More specifically, this exampledescribes the effects of polymer molecular weight (MW),lactide-glycolide (LG) ratio, and steroid load on the release profile oftriamcinolone acetonide (TA) or beclomethasone dipropionate (BD) frompoly(D,L-lactide-co-glycolide) polymer implants containing triamcinoloneacetonide (TA) or beclomethasone dipropionate (BD).

Drug release profiles of the present implants are related to themolecular weight (MW) of the polymer, such as PLGA in this example, thelactide-glycolide ratio (LG) of the polymer, and the drug load or amountof drug in the implant. Steroid release from the implants was examinedin phosphate buffered saline (pH 7.4; PBS) or citrate phosphate buffercontaining 0.1% cetyltrimethylammonium bromide (pH 5.4; CTAB).

In short, the implants were made by melt extrusion, and the steroidrelease from the implant was assayed by HPLC after incubation at 37° C.in phosphate buffered saline pH 7.4 or citrate phosphate buffer with0.1% cetyltrimethylammonium bromide pH 5.4. Triamcinalone release fromthe implants was monitored for 90 days, and beclomethasone dipropionaterelease from implants was monitored for 35 days.

The results of these experiments show that both steroids release muchfaster in the citrate buffer compared to the phosphate buffer. Duringthe first 30 days, the release profiles of the two steroids are verysimilar even though triamcinolone acetonide is about 150 times morewater soluble than beclomethasone dipropionate. Polymer properties havea minor effect on the release profile in this time frame or portion ofthe release profile (e.g, within approximately the first 30 days). Inthis early phase, the release appears to be controlled by the drugdissolution. The polymer propertiest become more important after thefirst 30 days or during a second time frame or portion of the releaseprofile as the polymer's hydrolysis rate differences become moreimportant.

Triamcinalone acetonide was obtained from Pharmacia Upjohn Co.Beclomethasone dipropionate was obtained from Sigma. PLGA polymersRG502, RG504, RG752, and RG755 were obtained from Boehringer-IngelheimPharma GmbH & Co. (Germany). Saline solution (0.9% NaCl) was obtainedfrom VWR Scientific. Cetyltrimethylammonium bromide (CTAB) was obtainedfrom Aldrich.

The following equipment was used: a ball mill (model mm200; F. KurtRetsch GmbH & Co., Germany); a turbula shaker (model T2F Nr.990720, GlenMills, Inc., New Jersey); a piston extruder obtained from APSEngineering, Inc.; a compactor (model A-1024, Jamesville Tool &Manufacturing, Inc., Milton Wis.); a shaking water bath (model 50,Precision Scientific, Winchester, Va.); a high pressure liquidchromatograph (HPLC, model Alliance 2695, Equipped with a Waters 2497Dual Wavelength Absorbance Detector, Waters, Inc., Milford, Mass.); andan oven (model 1330F, VWR Scientific, Cornelius, Oreg.).

In this example, implants were produced by an extrusion process.Steroids and polymer(s) were combined in a stainless steel ball-millcapsule along with two stainless steel mixing balls. The capsule wasplaced on the ball mill for five minutes at 20 cps. The capsule wasremoved from the ball mill and the content was stirred with a spatula;then placed back on the ball mill. This was repeated for two morefive-minute cycles. The ball-mill capsule was then placed on a Turbulamixer for five minutes at 20 cps. The content of the capsule wastransferred in small increments to an extruder barrel fitted with a dieusing a spatula and a small stainless steel funnel. After eachincrement, the powder was compacted in the extruder barrel with thecompactor set at 50 psi. When the extruder barrel was full, it istransferred to the extruder and the extruder was heated to temperatureand allowed to equilibrate. The polymer steroid mixture was extrudedthrough the die at 0.025 in/min.; the resulting filament was cut intoapproximately four-inch lengths and placed into a 60-mL screw cap vial,which was placed in a laminated foil pouch with a desiccant pack.

The experimental conditions for the extrusions are shown in Table 5 andTable 6 for triamcinolone acetonide and beclomethasone dipropionate,respectively.

TABLE 5 Triamcinolone Acetonide/PLGA Extrusion Parameters CompactorDiameter of Extrusion Speed, Extrusion Polymer Polymer ratio, % DrugLoad, % Press, psi Die, um ″/min Temp, ° C. RG752 100 30 50 720 0.002595 RG752 100 50 50 720 0.0025 96 RG755 100 30 50 720 0.0025 97 RG755 10050 50 720 0.0025 96 RG502 100 30 50 720 0.0025 97 RG502 100 50 50 7200.0025 98 RG504 100 30 50 720 0.0025 94 RG504 100 50 50 720 0.0025 98RG755 100 50 50 720 0.0025 101 RG752 100 30 50 720 0.0025 87

TABLE 6 Beclomethasone/PLGA Extrusion Parameters Polymer CompactorDiameter of Extrusion Speed, Extrusion Polymer ratio, % Drug Loading, %Press, psi Die, um ″/min Temp*, ° C. RG755 100 30 50 720 0.0025 94 RG755100 50 50 720 0.0025  99-109 RG752 100 30 50 720 0.0025  95-100 RG752100 50 50 720 0.0025 96 RG504 100 30 50 720 0.0025 98 RG504 100 50 50720 0.0025 104-114 RG502 100 30 50 720 0.0025 89-99 RG502 100 50 50 7200.0025 95-96 RG755 100 50 50 720 0.0025 95 RG752 100 30 50 720 0.0025 95*The mixture of API (the active pharmaceutical ingredient, that is thedrug used) and polymer were left in the extruder at 90° C. for 10 minbefore extrusion was started.

The extruded filaments were cut into 1-mg weight rod-shaped implants(rods). Each rod was placed in a 60-mL vial with 50 mL of phosphatebuffered saline pH 7.4 or citrate phosphate buffer pH 5.4 with 0.1%cetyltrimethylammonium bromide (CTAB) in an oscillating water bath (50rpm) at 37° C. At each time point, the released steroid was assayed(n=6) by HPLC, and the solution was removed from the vial and replacedwith fresh buffer. The steroid release was measured after the followingdays: 1, 4, 7, 14, 21, 28, 35, 48 69, 77, and 90.

Triamcinlolone acetonide (TA) released from the PLGA(poly(lactide-co-glycolide) polymer implant was assayed by HPLC (Waters,Milford, Mass.) employing a Waters Symmetry C18, 4.6×75 mm, 3 μm column.The mobile phase was acetonitrile-water (35:65, v/v) with a flow rate of1.0 mL/min and an injection volume of 20 μL. Ultraviolet detection of TAwas done at 243 nm. The total run time was 10 min and the TA retentiontime was 4.0 min. Quantization was based on peak area and atriamcinolone acetonide standardization curve.

Beclomethasone dipropionate (BD) released from the PLGA polymer implantwas assayed by HPLC (Waters, Milford, Mass.) employing a Discovery HS F5C18, 4.6×150 mm, 5 μm column. The mobile phase was acetonitrile-water(85:15), v/v) with a flow rate of 0.8 mL/min and an injection volume of30 μL. Ultraviolet detection of BD was done at 240 nm. The total runtime was 5 min and BD retention time was 2.5 min. Quantization was basedon peak area and a BD standardization curve.

The results from the design were analyzed qualitatively at three timesduring the dissolution—early, middle and late.

The triamcinolone acetonide release results are shown in Tables 7-10 andin FIGS. 18 to 21, respectively.

As shown, TA released into the CTAB buffer faster than it was releasedinto the PBS buffer. Drug release rate can also be effected by pH andsurfactant which can alter the polymer's hydrolysis rate and thereforethe drug release rate.

The drug load in the polymer has the largest positive effect on the drugrelease rate compared to MW and LG ratio for the first 30 days. Afterthe first 30 days, the LG ratio dominated the drug release rate andshowed a negative effect. In other words, a higher LG ratio resulted ina slower drug release. Without wishing to be bound by any particulartheory or mechanism of action, these effects may be related to high drugloading early in the dissolution resulting in more available drug at thepolymeric implant's surface. As drug becomes less available, the drugrelease rate may be controlled by the hydrolysis of the polymer, whichis faster for the lower LG ratio polymer.

Molecular weight of the polymer had a positive effect on drug releaserate especially later in the dissolution—faster release was observedwith higher MW polymers. While not wishing to be bound by any particulartheory or mechanism of action, this may occur because the lower MWpolymer pack more densely, and the higher MW polymer hydrolyze faster.Overall, the data show that early drug release is controlled by the drugload but the later in time drug release rate is controlled by thepolymer hydrolysis rate.

TABLE 7 Triamcinolone Release Results in Phosphate Buffered Saline pH7.4 for 30% Drug Load 755-30 752-30 504-30 502-30 752-30R Total release(%) 1 1.08 0.81 1.75 0.74 0.46 4 1.40 1.02 2.13 0.94 0.49 7 1.56 1.082.29 1.00 0.59 14 1.70 1.10 2.47 1.11 0.60 21 1.92 1.28 2.86 1.47 0.6928 2.05 1.37 4.14 2.77 0.97 35 2.08 1.41 9.73 4.60 1.06 48 2.22 1.9813.74 7.73 1.65 69 14.03 4.42 21.70 11.70 3.98 90 20.94 7.82 36.46 21.227.05 Standard Deviation 1 0.08 0.12 0.14 0.04 0.09 4 0.05 0.11 0.13 0.040.03 7 0.04 0.04 0.06 0.04 0.03 14 0.03 0.02 0.07 0.05 0.02 21 0.03 0.030.03 0.01 0.04 28 0.05 0.03 0.19 0.02 0.11 35 0.02 0.03 1.09 0.09 0.0548 0.12 0.03 0.83 0.33 0.10 69 1.87 0.06 2.09 0.73 0.25 90 0.34 0.943.05 3.10 0.53

TABLE 8 Triamcinolone Release Results in Phosphate Buffered Saline pH7.4 for 50% Drug Load 755-50 752-50 504-50 502-50 755-50R Total release(%) 1 1.83 2.01 1.88 1.97 2.20 4 2.93 2.32 2.56 2.57 3.75 7 3.68 2.442.74 2.84 4.62 14 4.66 2.58 2.93 3.09 5.68 21 5.23 2.73 3.16 3.46 6.2128 5.60 2.87 4.29 4.23 6.62 35 5.75 2.98 6.37 4.92 6.84 48 5.92 3.708.07 7.44 7.04 69 7.69 5.35 14.47 10.79 7.84 90 9.42 7.38 39.38 33.668.59 Standard Deviation 1 0.35 0.15 0.72 0.09 0.16 4 0.09 0.05 0.32 0.080.14 7 0.15 0.05 0.10 0.04 0.16 14 0.12 0.06 0.08 0.05 0.11 21 0.09 0.030.09 0.03 0.04 28 0.05 0.06 0.56 0.08 0.05 35 0.01 0.05 1.01 0.04 0.0348 0.04 0.09 1.58 2.65 0.03 69 0.79 0.25 3.75 2.60 0.08 90 0.47 0.372.45 3.63 0.08

TABLE 9 Triamcinolone Release Results in Citrate Phosphate Buffer pH 5.4for 30% Drug Load 755-30 752-30 504-30 502-30 752-30R Total release (%)1 1.79 1.93 2.50 1.07 0.69 4 2.18 1.93 2.85 1.12 0.74 7 2.35 2.22 3.031.13 0.86 14 2.61 3.05 3.23 1.21 0.94 21 3.00 4.62 4.73 1.59 0.96 283.45 12.44 16.60 7.99 1.00 35 3.57 12.59 45.16 25.70 1.00 48 4.05 12.9994.39 77.56 1.46 69 18.96 42.24 95.24 83.21 45.40 77 58.09 83.17 63.8390 92.97 96.82 79.93 Standard Deviation 1 0.19 1.11 0.12 0.05 0.05 40.03 0.00 0.02 0.04 0.03 7 0.06 0.26 0.04 0.02 0.01 14 0.05 1.18 0.020.03 0.03 21 0.21 2.06 0.04 0.02 0.02 28 0.27 3.92 0.27 0.64 0.03 350.07 0.06 2.99 2.69 0.00 48 0.27 0.04 3.90 2.92 0.04 69 0.48 3.20 0.503.24 2.29 77 2.48 6.49 2.71 90 3.88 5.73 4.08

TABLE 10 Triamcinolone Release Results in Citrate Phosphate Buffer pH5.4 for 50% Drug Load 755-50 752-50 504-50 502-50 755-50R Total release(%) 1 4.32 3.14 4.10 3.10 5.63 4 7.96 3.38 5.77 4.08 9.39 7 13.26 3.466.24 4.42 11.52 14 16.75 3.60 6.79 4.77 14.79 21 19.60 3.80 10.34 5.2516.43 28 21.91 3.90 20.94 9.17 17.21 35 23.75 4.02 41.21 16.58 17.59 4824.50 5.02 82.11 71.13 18.38 69 43.48 33.38 91.91 85.27 27.09 77 58.1754.68 35.62 90 85.58 75.87 54.43 Standard Deviation 1 1.01 0.63 0.140.14 1.76 4 0.76 0.09 0.36 0.08 0.09 7 5.93 0.05 0.17 0.03 0.07 14 1.160.03 0.13 0.03 0.15 21 1.23 0.03 0.32 0.03 0.12 28 2.78 0.02 0.14 0.550.11 35 2.20 0.03 1.66 3.08 0.06 48 0.34 0.19 3.58 13.62 0.10 69 8.477.52 4.47 1.67 1.65 77 1.78 7.97 1.13 90 5.86 11.33 4.57

The beclomethasone dipropionate release results are shown in Tables11-14 re plotted in FIGS. 22 to 25, respectively.

In these experiments, beclomethasone dipropionate release was examinedfor about one month. In this early timeframe (e.g., within about 1month), the release profiles for BD and TA were similar even though BDis about 150 times less soluble than TA. Changing to an acidic mediaincreased the amount of released BD slightly but not as much as the samemedium change did for TA. The BD release did not increase with increasedrug load in the phosphate buffer, but did in the CTAB buffer. Theresponse to increasing LG ratio was the same for both steroids for thefirst month. The effect is relatively small in the first 30 days butincreasing the LG ratio decreases the amount of drug released. Theeffect of MW was different for the two steroids; triamcinolone's releaseincreased slightly with higher MW in both media, whereasbeclomethasone's release decreased in PBS and increased in CTAB withincreasing MW.

TABLE 11 Beclomethasone Dipropionate Release Results in PhosphateBuffered Saline pH 7.4 for 30% Drug Load 755-30 752-30 504-30 502-30752-30R Total release (%) 1 0.31 0.34 1.23 1.46 0.72 4 1.86 3.07 2.902.75 2.27 7 2.64 3.74 3.64 3.52 3.22 14 3.03 4.36 4.12 3.95 3.58 21 3.564.92 4.80 4.61 4.13 28 4.11 5.32 6.09 5.53 4.62 35 4.45 5.80 6.82 6.685.03 48 69 90 Standard Deviation 1 0.05 0.41 0.35 0.06 0.19 4 0.57 0.280.48 0.34 0.22 7 0.12 0.43 0.28 0.26 0.22 14 0.17 0.09 0.16 0.21 0.28 210.27 0.18 0.18 0.08 0.11 28 0.14 0.44 0.51 0.16 0.12 35 0.16 0.16 0.130.11 0.15 48 69 90

TABLE 12 Beclomethasone Dipropionate Release Results in PhosphateBuffered Saline pH 7.4 for 50% Drug Load 755-50 752-50 504-50 502-50755-50R Total release (%) 1 0.11 0.18 0.70 1.01 0.75 4 0.78 1.95 2.222.00 1.84 7 1.13 2.78 2.57 2.50 2.34 14 1.29 3.19 2.91 2.75 2.72 21 1.623.68 3.25 3.21 3.20 28 1.88 4.15 3.87 3.72 3.56 35 2.02 4.42 4.22 4.363.75 48 69 90 Standard Deviation 1 0.07 0.09 0.24 0.30 0.07 4 0.37 0.190.16 0.14 0.17 7 0.12 0.10 0.30 0.18 0.16 14 0.04 0.09 0.08 0.08 0.08 210.09 0.08 0.20 0.10 0.04 28 0.15 0.11 0.12 0.16 0.08 35 0.08 0.17 0.150.19 0.03 48 69 90

TABLE 13 Beclomethasone Dipropionate Release Results in CitratePhosphate Buffer pH 5.4 for 30% Drug Load 755-30 752-30 504-30 502-30752-30R Total release (%) 1 0.28 1.20 2.16 1.28 1.37 4 1.44 1.54 3.161.59 1.50 7 2.15 1.87 3.90 2.04 1.93 14 2.62 2.06 4.53 2.39 2.27 21 3.052.35 7.45 3.68 2.54 28 3.32 2.50 12.51 7.09 2.82 Standard Deviation 10.16 0.22 0.23 0.25 0.10 4 0.24 0.11 0.22 0.16 0.11 7 0.15 0.09 0.170.03 0.08 14 0.09 0.21 0.08 0.11 0.06 21 0.09 0.05 0.24 0.16 0.16 280.10 0.22 0.74 0.29 0.07

TABLE 14 Beclomethasone Dipropionate Release Results in CitratePhosphate Buffer pH 5.4 for 50% Drug Load F755-50 752-50 504-50 502-50755-50R Total release (%) 1 2.01 0.47 3.07 2.16 3.80 4 6.26 1.77 6.013.16 7.64 7 9.00 2.55 7.48 3.98 10.30 14 12.40 3.51 8.45 4.73 13.49 2114.16 4.06 10.59 6.04 15.06 28 15.07 4.44 15.31 9.21 15.95 StandardDeviation 1 0.36 0.06 0.74 0.37 0.42 4 0.63 0.24 0.51 0.27 0.61 7 0.540.18 0.17 0.16 0.58 14 0.49 0.66 0.15 0.18 0.65 21 0.26 0.15 0.28 0.120.22 28 0.13 0.12 0.79 0.29 0.08

Based on these results, the release of low water soluble steroids fromPLGA implants is primarily limited by the dissolution of the steroid inthe first thirty days, and not the loading or amount of the steroid, orthe polymer matrix properties. In the early part of the dissolution(e.g., during the first portion of the drug release profile), therelease rates of the two steroids are very similar even though theirsolubilities are quite different. During this period the drug releaserate appears to be controlled by the steroid dissolution with thepolymer properties having a minor effect. Later in the dissolution(e.g., during a second portion of the drug release profile), the steroidrelease is more dependent on polymer properties as the hydrolysis ratesof the polymers become more important. Changing to a lower pH media witha lower surface tension increases the amount released for both steroids.

The present invention also encompasses the use of any and all possiblecombinations of the therapeutic agents disclosed herein in themanufacture of a medicament, such as a drug delivery system orcomposition comprising such a drug delivery system, to treat one or moreocular conditions, including those identified above.

All references, articles, publications and patents and patentapplications cited herein are incorporated by reference in theirentireties.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be variously practiced within thescope of the following claims.

1. A biodegradable intraocular implant comprising a steroid associatedwith a biodegradable polymer in the form of an intraocular implant, theimplant having a steroid release-rate profile, the release-rate profilehaving a first portion in which the steroid is released substantiallyindependently of a hydrolytic property of the biodegradable polymer, anda second portion in which the steroid release is more dependent on thehydrolytic property of the biodegradable polymer than during the firstportion, wherein the biodegradable polymer comprises a combination of aslow degrading poly(D,L-lactide) polymer and a fast degradingpoly(D,L-lactide-co-glycolide) polymer, wherein the slow degradingpoly(D,L-lactide) polymer has terminal free acid groups and a molecularweight of about 10-20 kD and the fast degradingpoly(D,L-lactide-co-glycolide) polymer has a 50:50 D,L-lactide toglycolide ratio, terminal free acid groups, and a molecular weight ofabout 9-40 kD.
 2. The implant of claim 1, wherein the steroid isdexamethasone.
 3. The implant of claim 1, wherein the first portion ofthe release-rate profile corresponds to a time period from about 1 dayto about 30 days after placement of the implant in a liquid environment.4. The implant of claim 3, wherein the second portion corresponds to atime period from about 30 days to about 90 days after placement of theimplant in the liquid environment.
 5. The implant of claim 1, whereinthe first portion of the release-rate profile corresponds to a timeperiod when less than 10% of the steroid is released from the implant.6. The implant of claim 5, wherein the second portion corresponds to atime period when less than 40% of the steroid is released from theimplant.
 7. The implant of claim 5, wherein the second portioncorresponds to a time period when less than 100% of the steroid isreleased from the implant.
 8. The implant of claim 1, wherein theimplant releases the steroid in a therapeutically effective amountwithout the patient developing a cataract.
 9. A biodegradableintraocular implant comprising a steroid associated with a biodegradablepolymer in the form of an intraocular implant, the implant having asteroid release-rate profile, the release-rate profile having a firstportion in which the steroid is released substantially independently ofa hydrolytic property of the biodegradable polymer, and a second portionin which the steroid release is more dependent on the hydrolyticproperty of the biodegradable polymer than during the first portion,wherein said biodegradable polymer comprises a slow degradingpoly(lactide) polymer and a fast degrading poly(lactide-coglycolide)polymer, wherein the poly(lactide-co-glycolide) and poly(lactide)polymers have terminal free acid groups.
 10. The implant of claim 9,wherein the steroid is selected from the group consisting ofbeclomethasone, beclomethasone dipropionate, and dexamethasone.
 11. Theimplant of claim 9, wherein the steroid is beclomethasone dipropionate.